The DOI matches its Crossref record; 144 of the 144 references it cites were found in a registry or an index; 14 of the 107 sources its claims cite were checked for support.
CRISPR-based functional genomics for neurological disease
Open accessAbstract
Neurodegenerative, neurodevelopmental and neuropsychiatric disorders are among the greatest public health challenges, as many lack disease-modifying treatments. A major reason for the absence of effective therapies is our limited understanding of the causative molecular and cellular mechanisms. Genome-wide association studies are providing a growing catalogue of disease-associated genetic variants, and the next challenge is to elucidate how these variants cause disease and to translate this understanding into therapies. This Review describes how new CRISPR-based functional genomics approaches can uncover disease mechanisms and therapeutic targets in neurological diseases. The bacterial CRISPR system can be used in experimental disease models to edit genomes and to control gene expression levels through CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa). These genetic perturbations can be implemented in massively parallel genetic screens to evaluate the functional consequences for human cells. CRISPR screens are particularly powerful in combination with induced pluripotent stem cell technology, which enables the derivation of differentiated cell types, such as neurons and glia, and brain organoids from cells obtained from patients. Modelling of disease-associated changes in gene expression via CRISPRi and CRISPRa can pinpoint causal changes. In addition, genetic modifier screens can be used to elucidate disease mechanisms and causal determinants of cell type-selective vulnerability and to identify therapeutic targets.
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Claims the paper makes
62 Not checked yet · 29 Own interpretation · 19 No basis given · 4 Partly supported · 1 Couldn’t confirm · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“First, there are differences between disease-relevant cell types, such as neurons and glia, between humans and mice.”
§ CRISPR-based functional genomics for neurological disease > Current challenges > Limitations of animal models of disease
What the sources say
- Partly supportedcites [18] Burbulla, L. F. et al. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science 357, 1255–1261 (2017). sourceExperimental — accuracy not yet measured
The section ‘Altered calcium and dopamine metabolism contribute to differences between human and mouse neurons’ reports differences in dopaminergic neurons between the species. The cited paper does not establish the claim for glia or disease-relevant cell types more generally; no page number is available in our copy. (LLM, conf=0.85)
- Not checked yetcites [10] Seeley, W. W. et al. Early frontotemporal dementia targets neurons unique to apes and humans. Ann. Neurol. 60, 660–667 (2006). source
- Partly supportedcites [19] Gosselin, D. et al. An environment-dependent transcriptional network specifies human microglia identity. Science 356, eaal3222 (2017). sourceExperimental — accuracy not yet measured
The Human microglia transcriptomes section reports species-specific gene-expression differences in microglia, including genes linked to human neurological disorders. The paper supports the claim for microglia, a type of glial cell, but the cited passages do not establish corresponding differences in neurons or glia more broadly. (LLM, conf=0.87)
- Supportedcites [20] Friedman, B. A. et al. Diverse brain myeloid expression profiles reveal distinct microglial activation states and aspects of Alzheimer’s disease not evident in mouse models. Cell Rep. 22, 832–847 (2018). source
The Results report greater variability in cell-type scores in human tissues than in mouse models and discuss scores for neurons, astrocytes, and myeloid cells. The Discussion also identifies differences between human Alzheimer’s disease tissue and mouse models in myeloid-related expression. These findings support the broad comparison, in the context of the tissues and models studied. (LLM, conf=0.86)
plainstates an association- Asserted: passes — The authors put it forward as true.
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- Partly supported
None of the sources cited for this claim have been checked yet.
In the paper
“While screens based on survival or FACS monitor low-dimensional phenotypes, pooled CRISPR screens can also be coupled to single-cell RNA sequencing to provide high-dimensional readouts of the effects of gene perturbation72–75”
§ CRISPR-based functional genomics for neurological disease > CRISPR screens in mammalian cells > Pooled genetic screens
What the sources say
- Could not verifycites [72] Rauch, J. N. et al. LRP1 is a master regulator of tau uptake and spread. Nature 580, 381–385 (2020). sourceExperimental — accuracy not yet measured
The Methods (Cell Culture and Tau Uptake Assay; page unavailable) describe CRISPRi perturbations and flow-cytometry measurements of tau uptake. Searches for single-cell RNA sequencing, transcriptomic readouts, and pooled CRISPR screens found no passage in our copy linking pooled screens to single-cell RNA sequencing or high-dimensional readouts. (LLM, conf=0.73)
- Could not verifycites [73] Chen, J. J. et al. Compromised function of the ESCRT pathway promotes endolysosomal escape of tau seeds and propagation of tau aggregation. J. Biol. Chem. 294, 18952–18966 (2019). sourceExperimental — accuracy not yet measured
The Figure 2 caption (p. 5) and Primary CRISPRi screen methods (p. 12) describe a pooled screen read out by FRET-based FACS and sequencing of sgRNA cassettes. Searches for single-cell RNA sequencing, transcriptomics, and Perturb-seq found no passage describing the claimed coupling or its high-dimensional readouts. The References (p. 16) list a single-cell CRISPR screening paper, but that citation alone does not establish the claim in this paper's text. (LLM, conf=0.78)
- Not checked yetcites [74] Rousseaux, M. W. C. et al. A druggable genome screen identifies modifiers of α-synuclein levels via a tiered cross-species validation approach. J. Neurosci. 38, 9286–9301 (2018). source
- Could not verifycites [75] Vazquez-Velez, G. E. et al. Doublecortin-like kinase 1 regulates α-synuclein levels and toxicity. J. Neurosci. 40, 459–477 (2020). sourceExperimental — accuracy not yet measured
The Introduction describes an shRNA screen, and the RNA extraction and cDNA production section describes qPCR measurements. Searches for pooled CRISPR screens and single-cell RNA sequencing found no passage in our copy addressing their combination or its high-dimensional readouts. Page numbers were not available in the indexed passages. (LLM, conf=0.75)
plainstates a cause- Asserted: passes — The authors put it forward as true.
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- Could not verify
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“As a case in point, there was little correlation between genes found to control sensitivity to toxic dipeptide repeats in cancer cells versus primary neurons63.”
§ CRISPR-based functional genomics for neurological disease > Screens in iPSC-derived disease models
What the sources say
- Could not verifycites [63] Shalem, O. et al. Genome-scale CRISPR-Cas9 knockout screening in human cells. Science 343, 84–87 (2014). sourceExperimental — accuracy not yet measured
The paper’s screening passages (indexed as Abstract; page unavailable) describe genes affecting viability and vemurafenib resistance in human cells. Searches for toxic dipeptide repeats and a cancer-cell versus primary-neuron comparison found no passage addressing the claimed correlation. (LLM, conf=0.78)
plain- Asserted: passes — The authors put it forward as true.
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- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“APOE ε4 also affects properties of iPSC-derived astrocytes and microglia, notably reducing their ability to clear Aβ9,102.”
§ CRISPR-based functional genomics for neurological disease > Screens in iPSC-derived disease models > iPSC-derived cellular disease models
What the sources say
- Supportedcites [9] Lin, Y. T. et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron 98, 1141–1154 (2018). source
The Results section reports reduced Aβ42 uptake and lysosome-dependent degradation in APOE4 iPSC-derived astrocytes. It also reports less efficient Aβ42 uptake by APOE4 microglia-like cells and more extracellular Aβ aggregates in organoids co-cultured with them. The Discussion summarizes these findings as impaired astrocyte- and microglia-mediated Aβ clearance. (LLM, conf=0.93)
- Could not verifycites [102] Brownjohn, P. W. et al. Functional studies of missense TREM2 mutations in human stem cell-derived microglia. Stem Cell Rep. 10, 1294–1307 (2018). sourceExperimental — accuracy not yet measured
The Introduction discusses TREM2 binding to apolipoproteins, and the Results discuss uptake of acetylated LDL by TREM2-mutant microglia. Neither passage addresses APOE ε4, iPSC-derived astrocytes, or reduced Aβ clearance in those cells (searched: APOE ε4 and Aβ clearance). (LLM, conf=0.74)
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The underlying mechanisms are not understood.”
§ CRISPR-based functional genomics for neurological disease > Current challenges > Key mechanistic questions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Third, an arrayed longitudinal imaging screens uncovered consequences of gene knockdown for neuron-specific morphological features, such as neurite length and branching patterns76, which could not have been evaluated in other cell types.”
§ CRISPR-based functional genomics for neurological disease > Screens in iPSC-derived disease models > CRISPR screens in iPSC-derived cells
What the sources say
- Not checked yetcites [76] Potting, C. et al. Genome-wide CRISPR screen for PARKIN regulators reveals transcriptional repression as a determinant of mitophagy. Proc. Natl Acad. Sci. USA 115, E180–E189 (2018). source
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Recently, we implemented large-scale CRISPR-based genetic screens for the first time in a human iPSC-derived differentiated cell type, namely neurons76.”
§ CRISPR-based functional genomics for neurological disease > Screens in iPSC-derived disease models > CRISPR screens in iPSC-derived cells
What the sources say
- Not checked yetcites [76] Potting, C. et al. Genome-wide CRISPR screen for PARKIN regulators reveals transcriptional repression as a determinant of mitophagy. Proc. Natl Acad. Sci. USA 115, E180–E189 (2018). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Second, housekeeping genes that were essential for survival of both iPSCs and neurons may play different roles in the two cell types, based on vastly different transcriptomic consequences of their knockdown76.”
§ CRISPR-based functional genomics for neurological disease > Screens in iPSC-derived disease models > CRISPR screens in iPSC-derived cells
What the sources say
- Not checked yetcites [76] Potting, C. et al. Genome-wide CRISPR screen for PARKIN regulators reveals transcriptional repression as a determinant of mitophagy. Proc. Natl Acad. Sci. USA 115, E180–E189 (2018). source
hedgedstates a possible cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“CRISPR screening recovered a previously known key regulator of neuronal cell death, MAP3K12/DLK76.”
§ CRISPR-based functional genomics for neurological disease > Screens in iPSC-derived disease models > CRISPR screens in iPSC-derived cells
What the sources say
- Not checked yetcites [76] Potting, C. et al. Genome-wide CRISPR screen for PARKIN regulators reveals transcriptional repression as a determinant of mitophagy. Proc. Natl Acad. Sci. USA 115, E180–E189 (2018). source
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“First, the set of genes controlling survival of neurons were distinct from those controlling cancer cell or iPSC survival.”
§ CRISPR-based functional genomics for neurological disease > Screens in iPSC-derived disease models > CRISPR screens in iPSC-derived cells
What the sources say
- Not checked yetcites [76] Potting, C. et al. Genome-wide CRISPR screen for PARKIN regulators reveals transcriptional repression as a determinant of mitophagy. Proc. Natl Acad. Sci. USA 115, E180–E189 (2018). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 35
- Probably not a substantial claim. 18
- The quote only partly states this claim. 1
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Non-coding risk variants in humans often occur in non-conserved sequences in the genome, precluding direct mouse modeling of these variants, and it is challenging to determine through which coding gene or genes these variants affect disease risk3.”
§ CRISPR-based functional genomics for neurological disease > Current challenges > Limitations of animal models of disease
What the sources say
- Partly supportedcites [3] Pimenova, A. A., Raj, T. & Goate, A. M. Untangling genetic risk for Alzheimer’s disease. Biol. Psychiatry 83, 300–310 (2018). sourceExperimental — accuracy not yet measured
The Functional Genomics section says GWAS loci can contain multiple genes and that GWAS alone cannot establish which gene is causal, supporting the difficulty of identifying the affected gene. The paper does not say that human non-coding risk variants often occur in non-conserved sequences or that this precludes direct mouse modeling; its Future Directions section instead proposes mouse models for functional validation. Page numbers were not available in our copy. (LLM, conf=0.86)
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Furthermore, iPSC-derived cell types from different lineages can be combined into defined three-dimensional cultures, termed assembloids9,94–98.”
§ CRISPR-based functional genomics for neurological disease > Screens in iPSC-derived disease models > iPSC technology
What the sources say
- Partly supportedcites [9] Lin, Y. T. et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron 98, 1141–1154 (2018). sourceExperimental — accuracy not yet measured
The Results section ('APOE4 organoids accumulate Aβ and exhibit elevated tau phosphorylation'; page unavailable) describes iPSC-derived organoids as 3D cultures that eventually contain both neurons and astrocytes. It does not describe combining separately derived cell lineages into a defined culture or call such cultures assembloids. (LLM, conf=0.86)
- Could not verifycites [94] Chai, N. et al. Genome-wide synthetic lethal CRISPR screen identifies FIS1 as a genetic interactor of ALS-linked C9ORF72. Brain Res. 1728, 146601 (2020). sourceExperimental — accuracy not yet measured
The Cell culture and Synthetic lethal screen sections describe PMA-differentiated U937 cells, not iPSC-derived cells combined across lineages. Searches for assembloids, three-dimensional cultures, and iPSC-derived organoids found no passage addressing the claim in our copy; page numbers were unavailable. (LLM, conf=0.76)
- Not checked yetcites [95] Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006). source
- Not checked yetcites [96] Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007). source
- Could not verifycites [97] Sproul, A. A. et al. Generation of iPSC lines from archived non-cryoprotected biobanked dura mater. Acta Neuropathol. Commun. 2, 4 (2014). sourceExperimental — accuracy not yet measured
The Methods (In vitro pluripotency assay) describe forming embryoid bodies from iPSCs, and the Results describe markers of three germ layers and neuronal differentiation. Neither passage addresses combining separately derived cell types into defined three-dimensional cultures called assembloids; searches for assembloids and combined lineages found no such passage. (LLM, conf=0.76)
- Could not verifycites [98] Vierbuchen, T. et al. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463, 1035–1041 (2010). sourceExperimental — accuracy not yet measured
The Discussion describes direct conversion of mouse fibroblasts into neurons, and the Methods Summary describes glial and cortical co-cultures. Neither addresses combining iPSC-derived cells from different lineages into defined three-dimensional cultures. Searches for “assembloids” and three-dimensional iPSC co-cultures found no supporting passage; page numbers were unavailable in our copy. (LLM, conf=0.75)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
In the paper
“A prominent example was the ubiquitin-activating E1 enzyme UBA176.”
§ CRISPR-based functional genomics for neurological disease > Screens in iPSC-derived disease models > CRISPR screens in iPSC-derived cells
What the sources say
- Not checked yetcites [76] Potting, C. et al. Genome-wide CRISPR screen for PARKIN regulators reveals transcriptional repression as a determinant of mitophagy. Proc. Natl Acad. Sci. USA 115, E180–E189 (2018). source
plainstates an association- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
None of the sources cited for this claim have been checked yet.
In the paper
“mouse and human microglia, which have recently emerged as key players in Alzheimer’s Disease and other neurodegenerative diseases, show differences in particular in the expression of disease-relevant genes19, and they adopt distinctly different states in human diseased brains compared to mouse models20.”
§ CRISPR-based functional genomics for neurological disease > Current challenges > Limitations of animal models of disease
What the sources say
- Not checked yetcites [19] Gosselin, D. et al. An environment-dependent transcriptional network specifies human microglia identity. Science 356, eaal3222 (2017). source
- Not checked yetcites [20] Friedman, B. A. et al. Diverse brain myeloid expression profiles reveal distinct microglial activation states and aspects of Alzheimer’s disease not evident in mouse models. Cell Rep. 22, 832–847 (2018). source
plainstates an association- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Answers to these questions have important implications for our understanding of disease mechanisms, and should clarify which therapeutic strategies are likely to be effective and disease-modifying.”
§ CRISPR-based functional genomics for neurological disease > Current challenges > Key mechanistic questions
hedgedstates a possible cause- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“Intriguingly, these two mechanisms may synergize in disease7.”
§ CRISPR-based functional genomics for neurological disease > Current challenges > Key mechanistic questions
What the sources say
- Not checked yetcites [7] Boivin, M. et al. Reduced autophagy upon C9ORF72 loss synergizes with dipeptide repeat protein toxicity in G4C2 repeat expansion disorders. EMBO J. 39, e100574 (2020). source
hedgedstates a possible cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“if processes driving age-associated neurological diseases are initiated early in life, therapeutic intervention may need to start similarly early.”
§ CRISPR-based functional genomics for neurological disease > Current challenges > Key mechanistic questions
hedgedstates a possible cause- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“therefore genetic changes can have pleiotropic effects, and a major challenge is to understand which of these effects are relevant for disease.”
§ CRISPR-based functional genomics for neurological disease > Current challenges > Key mechanistic questions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Rests on an assumption: For many human genes, the molecular and cellular functions of the gene product are not well understood, and many genes have multiple functions, so genetic changes can have pleiotropic effects.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“An understanding of the factors that make some neurons vulnerable and others comparatively resilient to disease could inform therapeutic strategies aimed at increasing resilience of vulnerable neuronal populations.”
§ CRISPR-based functional genomics for neurological disease > Current challenges > Key mechanistic questions
hedgedstates a possible cause- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
- Rests on an assumption: Selective vulnerability of specific cell types is a hallmark of many neurological diseases and drives disease-specific symptoms.
In the paper
“Coding variants that are disease-causing in humans may not cause disease in mice: the A53T mutation in alpha-synuclein is linked to Parkinson’s Disease in humans but corresponds to the wild-type residue in mice, and mouse models of A53T alpha-synuclein rely on overexpression of human proteins21.”
§ CRISPR-based functional genomics for neurological disease > Current challenges > Limitations of animal models of disease
What the sources say
- Not checked yetcites [21] Giasson, B. I. et al. Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron 34, 521–533 (2002). source
plainstates a possible cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“dopaminergic neurons, which are selectively vulnerable in Parkinson’s Disease, contain substantially higher levels of dopamine in humans compared to mice, and some cellular disease processes have been proposed to depend on the high levels of dopamine found only in human dopaminergic neurons18.”
§ CRISPR-based functional genomics for neurological disease > Current challenges > Limitations of animal models of disease
What the sources say
- Not checked yetcites [18] Burbulla, L. F. et al. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science 357, 1255–1261 (2017). source
hedgedstates a possible cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“advances in imaging technologies, including magnetic resonance imaging and positron emission tomography with specific molecular tracers, have enabled longitudinal tracking of disease progression in patient brains, but interventions to establish causality are only possible in the context of clinical trials.”
§ CRISPR-based functional genomics for neurological disease > Current challenges > Limitations of patient tissue studies
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Experimental results support toxicity of RNAs containing the expanded repeat, as well as toxicity of dipeptide repeat translated from these RNAs, but also to haploinsufficiency of the C9orf72 protein as a cause of disease6.”
§ CRISPR-based functional genomics for neurological disease > Current challenges > Key mechanistic questions
What the sources say
- Not checked yetcites [6] Balendra, R. & Isaacs, A. M. C9orf72-mediated ALS and FTD: multiple pathways to disease. Nat. Rev. Neurol. 14, 544–558 (2018). source
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A functional and mechanistic understanding will be key to translating findings from human genetics to effective therapies.”
§ CRISPR-based functional genomics for neurological disease > Introduction
plainstates a possible cause- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
In the paper
“Disease-associated mutations are often found in proteins that are expressed broadly (such as tau, which is expressed in all neurons), yet specific subpopulations are selectively affected by downstream processes (such as the Von Economo neurons in frontotemporal dementia10).”
§ CRISPR-based functional genomics for neurological disease > Current challenges > Key mechanistic questions
What the sources say
- Not checked yetcites [10] Seeley, W. W. et al. Early frontotemporal dementia targets neurons unique to apes and humans. Ann. Neurol. 60, 660–667 (2006). source
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“More recently, iPSCs were successfully obtain from post-mortem human brain tissue, specifically dura mater fibroblasts91.”
§ CRISPR-based functional genomics for neurological disease > Screens in iPSC-derived disease models > iPSC technology
What the sources say
- Not checked yetcites [91] Ridge, P. G. et al. Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience. Genome Med. 9, 100 (2017). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Such screens provide rich information on cellular processes such as differentiation72, immune responses72,73,75, stress responses74 and compensatory responses76 and enable high-throughput mapping of regulatory elements77.”
§ CRISPR-based functional genomics for neurological disease > CRISPR screens in mammalian cells > Pooled genetic screens
What the sources say
- Not checked yetcites [72] Rauch, J. N. et al. LRP1 is a master regulator of tau uptake and spread. Nature 580, 381–385 (2020). source
- Not checked yetcites [74] Rousseaux, M. W. C. et al. A druggable genome screen identifies modifiers of α-synuclein levels via a tiered cross-species validation approach. J. Neurosci. 38, 9286–9301 (2018). source
- Not checked yetcites [77] Cheng, W. et al. CRISPR-Cas9 screens identify the RNA helicase DDX3X as a repressor of C9ORF72 (GGGGCC)n repeat-associated non-AUG translation. Neuron 104, 885–898 (2019). source
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“CRISPR enables the rapid generation of a site-specific nuclease by combining the Cas9 protein (or functionally similar proteins from other microbial species) with a single guide RNA (sgRNA) that directs Cas9 to the desired target site.”
§ CRISPR-based functional genomics for neurological disease > CRISPR-based gene perturbation > Genome editing
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“used to generate models of neurological and related diseases: disruption of the dystrophin gene to model Duchenne muscular dystrophy29, disruption of the MCPH1 gene to model microcephaly30, and disruption of the MECP2 gene to model Rett syndrome31.”
§ CRISPR-based functional genomics for neurological disease > Current challenges > Limitations of animal models of disease
What the sources say
- Not checked yetcites [29] Chen, Y. et al. Functional disruption of the dystrophin gene in rhesus monkey using CRISPR/Cas9. Hum. Mol. Genet. 24, 3764–3774 (2015). source
- Not checked yetcites [30] Ke, Q. et al. TALEN-based generation of a cynomolgus monkey disease model for human microcephaly. Cell Res. 26, 1048–1061 (2016). source
- Not checked yetcites [31] Chen, Y. et al. Modeling Rett syndrome using TALEN-edited MECP2 mutant cynomolgus monkeys. Cell 169, 945–955 (2017). source
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, experiments in animals, in particular non-human primates, are time-consuming, costly, and have important ethical considerations, limiting their scalability for the investigation of the large number of disease-associated variants that are being uncovered.”
§ CRISPR-based functional genomics for neurological disease > Current challenges > Limitations of animal models of disease
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“When a double-stranded break is introduced into genomic DNA, cells can repair the break by using a DNA molecule with high sequence similarity as a template. If an artificial template is provided while the DNA break is introduced, this pathway provides a mean to incorporate desired DNA sequences into the genome34,35”
§ CRISPR-based functional genomics for neurological disease > CRISPR-based gene perturbation > Genome editing
What the sources say
- Not checked yetcites [34] Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013). source
- Not checked yetcites [35] Mali, P. et al. RNA-guided human genome engineering via Cas9. Science 339, 823–826 (2013). Together with Cong et al. (2013), this study demonstrates the use of CRISPR–Cas9-based genome engineering in human cells. source
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“CRISPR technology is based on a prokaryotic antiviral defense system characterized by DNA elements termed CRISPRs (clustered regularly interspaced short palindromic repeats) and CRISPR-associated (Cas) proteins. CRISPRs are derived from bacteriophage genomes and generate RNAs that function with Cas proteins to cleave bacteriophage genomes upon infection32.”
§ CRISPR-based functional genomics for neurological disease > CRISPR-based gene perturbation
What the sources say
- Not checked yetcites [32] Hale, C. R. et al. RNA-guided RNA cleavage by a CRISPR RNA-Cas protein complex. Cell 139, 945–956 (2009). source
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“in practice, however, it is difficult to segment microscopic images of cells with complex morphologies, such as neurons and glia, which is a prerequisite for assigning all parts of a cell to the correct sgRNA.”
§ CRISPR-based functional genomics for neurological disease > CRISPR screens in mammalian cells > Arrayed genetic screens
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Fibroblasts can also be directly reprogrammed into differentiated cell types such as neurons92.”
§ CRISPR-based functional genomics for neurological disease > Screens in iPSC-derived disease models > iPSC technology
What the sources say
- Not checked yetcites [92] Finch, N. et al. TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology 76, 467–474 (2011). source
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Even though such screens have been able to uncover genes that were then validated in relevant cell types such as neurons63,65,68, they have obvious limitations for the study of neurological disease.”
§ CRISPR-based functional genomics for neurological disease > Screens in iPSC-derived disease models
What the sources say
- Not checked yetcites [63] Shalem, O. et al. Genome-scale CRISPR-Cas9 knockout screening in human cells. Science 343, 84–87 (2014). source
- Not checked yetcites [65] Hanna, R. E. et al. Massively parallel assessment of human variants with base editor screens. Preprint at bioRxiv https://doi.org/10.1101/2020.05.17.100818 (2020). source
- Not checked yetcites [68] Kramer, N. J. et al. CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity. Nat. Genet. 50, 603–612 (2018). source
plainstates a possible cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Most neurological diseases involve functional changes in specific nervous system cell types, and these functions can only be properly studied in those cell types.
None of the sources cited for this claim have been checked yet.
In the paper
“This approach was pioneered in mammalian cells using RNA interference80,81, but CRISPR-based platforms have enabled the generation of substantially larger genetic interaction maps82, including CRISPRa-based gain-of-function maps83 and maps that combine gain- and loss-of-function perturbations to map directional pathways84.”
§ CRISPR-based functional genomics for neurological disease > CRISPR screens in mammalian cells > Systematic genetic interaction screens
What the sources say
- Not checked yetcites [82] Tian, R. et al. CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons. Neuron 104, 239–255 (2019). This paper describes the use of a platform for large-scale CRISPR screens in neurons derived from human iPSCs. source
- Not checked yetcites [83] Gasperini, M. et al. A genome-wide framework for mapping gene regulation via cellular genetic screens. Cell 176, 377–390.e19 (2019). source
- Not checked yetcites [84] Mimitou, E. P. et al. Multiplexed detection of proteins, transcriptomes, clonotypes and CRISPR perturbations in single cells. Nat. Methods 16, 409–412 (2019). source
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“A recent example for a genetic interaction screen with relevance to neurological disease is a screen for genes loss of which was synthetic lethal with C9orf72 loss88. The strongest synthetic lethal gene was FIS1, which encodes a protein that mediating mitochondrial fission and mitophagy, and follow-up experiments also pointed to a role in regulating inflammatory signaling88.”
§ CRISPR-based functional genomics for neurological disease > CRISPR screens in mammalian cells > Systematic genetic interaction screens
What the sources say
- Not checked yetcites [88] Kampmann, M., Bassik, M. C. & Weissman, J. S. Integrated platform for genome-wide screening and construction of high-density genetic interaction maps in mammalian cells. Proc. Natl Acad. Sci. USA 110, E2317–E2326 (2013). source
plainstates an association- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Intriguingly, UBA1 is widely expressed in the human body, but loss-of-function mutations are linked to neurodegenerative diseases110.”
§ CRISPR-based functional genomics for neurological disease > Screens in iPSC-derived disease models > CRISPR screens in iPSC-derived cells
What the sources say
- Not checked yetcites [110] Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013). source
plainstates an association- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“For example, motor neurons are selectively vulnerable in amyotrophic lateral sclerosis (ALS).”
§ CRISPR-based functional genomics for neurological disease > Applications to neurological disease > Cell type-selective vulnerability
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
- Rests on an assumption: Many neurological disorders, especially neurodegenerative diseases, are characterized by selective vulnerability of specific cell types.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, it is not trivial to determine the genes through which a disease-associated eQTL affects disease processes. Even if the set of genes affected in their expression by a genetic variant is known, it is not clear which of these candidate genes is relevant for disease.”
§ CRISPR-based functional genomics for neurological disease > Applications to neurological disease > Causative changes in gene expression
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These disease-associated states are characterized by expression changes in numerous genes, but it is generally not clear which of these changes have either beneficial or detrimental effects in disease.”
§ CRISPR-based functional genomics for neurological disease > Applications to neurological disease > Causative changes in gene expression
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, linkage disequilibrium can make it difficult to assign causality to a specific genetic variant based on natural genetic variation in the human population, and the use of isogenic lines can overcome this problem.”
§ CRISPR-based functional genomics for neurological disease > Screens in iPSC-derived disease models > iPSC-derived cellular disease models
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“However, CRISPR-induced DNA breaks are particularly toxic to iPSCs111, reducing cell survival and potentially confounding the observed phenotypes.”
§ CRISPR-based functional genomics for neurological disease > Screens in iPSC-derived disease models > CRISPR screens in iPSC-derived cells
What the sources say
- Not checked yetcites [111] Soldner, F. et al. Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell 146, 318–331 (2011). source
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, most differentially expressed factors are likely to reflect the different functional specializations of neurons, and it is not clear which of these factors are causal determinants of vulnerability to specific diseases.”
§ CRISPR-based functional genomics for neurological disease > Applications to neurological disease > Cell type-selective vulnerability
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Intriguingly, the expression of ALS risk genes is not restricted to motor neurons, indicating that specific factors in the cellular environment of motor neurons make them more vulnerable to ALS.”
§ CRISPR-based functional genomics for neurological disease > Applications to neurological disease > Cell type-selective vulnerability
hedgedstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“eQTLs can affect the expression of nearby, but also distant genes, and their effect can be cell-type and cell-state specific.”
§ CRISPR-based functional genomics for neurological disease > Applications to neurological disease > Causative changes in gene expression
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“First, while small-molecule screens need to be implemented in an arrayed format and therefore require automation infrastructure, genetic screens for some phenotypes can be implemented as pooled screens, making them scalable to genome-wide screens without requiring automation.”
§ CRISPR-based functional genomics for neurological disease > Applications to neurological disease > Discovery of therapeutic targets
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“CRISPRi-based gene knockdown may result in weaker phenotypes than full gene knockout, however it is non-toxic in iPSCs and iPSC-derived cells76, inducible76 and reversible42, thereby enabling time-resolved analysis of gene function76.”
§ CRISPR-based functional genomics for neurological disease > Screens in iPSC-derived disease models > CRISPR screens in iPSC-derived cells
What the sources say
- Not checked yetcites [76] Potting, C. et al. Genome-wide CRISPR screen for PARKIN regulators reveals transcriptional repression as a determinant of mitophagy. Proc. Natl Acad. Sci. USA 115, E180–E189 (2018). source
- Not checked yetcites [42] Gilbert, L. A. et al. Genome-scale CRISPR-mediated control of gene repression and activation. Cell 159, 647–661 (2014). This paper describes the first platform for genome-wide CRISPRi and CRISPRa screens. source
hedgedstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A detailed understanding of the genes expression changes of which are detrimental would prioritize these genes as potential therapeutic targets.”
§ CRISPR-based functional genomics for neurological disease > Applications to neurological disease > Causative changes in gene expression
hedgedstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
In the paper
“CRISPRa evaluates gain-of-function phenotypes and can provide complementary insight to CRISPR knockout or CRISPRi-based loss-of-function screens42.”
§ CRISPR-based functional genomics for neurological disease > Screens in iPSC-derived disease models > CRISPR screens in iPSC-derived cells
What the sources say
- Not checked yetcites [42] Gilbert, L. A. et al. Genome-scale CRISPR-mediated control of gene repression and activation. Cell 159, 647–661 (2014). This paper describes the first platform for genome-wide CRISPRi and CRISPRa screens. source
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Conversely, mutations in alpha-synuclein can cause Parkinson’s Disease, where dopaminergic neurons in the substantia nigra are selectively vulnerable, but motor neurons are less vulnerable, even though alpha-synuclein is widely expressed in neurons.”
§ CRISPR-based functional genomics for neurological disease > Applications to neurological disease > Cell type-selective vulnerability
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Rests on an assumption: Many neurological disorders, especially neurodegenerative diseases, are characterized by selective vulnerability of specific cell types.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Second, while small-molecule screens yield compounds with beneficial effects, it is often a major challenge to identify their molecular targets and mechanism of action. By contrast, genetic screens directly identify relevant targets and mechanisms, for which effective compounds must then be developed.”
§ CRISPR-based functional genomics for neurological disease > Applications to neurological disease > Discovery of therapeutic targets
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“First, GWAS studies frequently uncover disease-associated genetic variants outside protein-coding regions. Such variants can affect the expression of other genes, thus acting as expression quantitative trait loci (eQTLs).”
§ CRISPR-based functional genomics for neurological disease > Applications to neurological disease > Causative changes in gene expression
plainstates a possible cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Neurons derived from familial as well as sporadic Alzheimer’s patient cells show enlarged early endosomes100, phosphorylated tau100, and increased production of Aβ peptides100 and oligomers101.”
§ CRISPR-based functional genomics for neurological disease > Screens in iPSC-derived disease models > iPSC-derived cellular disease models
What the sources say
- Not checked yetcites [100] Pasca, S. P. Assembling human brain organoids. Science 363, 126–127 (2019). source
- Not checked yetcites [101] Schwartz, M. P. et al. Human pluripotent stem cell-derived neural constructs for predicting neural toxicity. Proc. Natl Acad. Sci. USA 112, 12516–12521 (2015). source
plainstates an association- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“CRISPRi and CRISPRa enable the systematic control of the expression levels of specific genes in human cells.”
§ CRISPR-based functional genomics for neurological disease > Applications to neurological disease > Causative changes in gene expression
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CRISPR-based functional genomics enable the specific perturbation of genes of interests, thereby making it feasible to establish causality.”
§ CRISPR-based functional genomics for neurological disease > Conclusions and future directions
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Second, iPSC-derived neurons resemble young neurons, whereas many neurological disorders affect older neurons, and aging is the major risk factor for neurodegenerative diseases.”
§ CRISPR-based functional genomics for neurological disease > Conclusions and future directions
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Aging is the major risk factor for neurodegenerative diseases.
None of the sources cited for this claim have been checked yet.
In the paper
“Neurons directly reprogrammed from fibroblasts maintain some features reflecting the age of the donor and mirroring some properties of aged neurons120,121; however they are not readily obtained in quantities required for large-scale screens.”
§ CRISPR-based functional genomics for neurological disease > Conclusions and future directions
What the sources say
- Not checked yetcites [120] Deczkowska, A. et al. Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell 173, 1073–1081 (2018). source
- Not checked yetcites [121] Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017). source
plainstates an association- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
Many neurodegenerative, neurodevelopmental, and neuropsychiatric disorders lack disease-modifying treatments.
“Neurodegenerative, neurodevelopmental and neuropsychiatric disorders are among the greatest public health challenges, since many lack disease-modifying treatments.”
The paper relies on this without support.
Limited understanding of causative molecular and cellular mechanisms is a major reason for the lack of effective therapies.
“A major reason for this lack in effective therapies is our limited understanding of the causative molecular and cellular mechanisms.”
The paper relies on this without support.
Many GWAS risk variants are located outside coding regions and are typically thought to affect expression of one or several coding genes.
“Many risk variants identified in genome-wide association studies are located outside coding regions, and are typically thought to affect the expression of one or several coding genes.”
The paper relies on this without support.
For many human genes, the molecular and cellular functions of the gene product are not well understood, and many genes have multiple functions, so genetic changes can have pleiotropic effects.
“For many human genes, the molecular and cellular functions of the gene product are not well understood, and many genes have multiple functions – therefore genetic changes can have pleiotropic effects”
The paper relies on this without support.
Selective vulnerability of specific cell types is a hallmark of many neurological diseases and drives disease-specific symptoms.
“The selective vulnerability of specific cell types is a hallmark of many neurological diseases and drives disease-specific symptoms.”
The paper relies on this without support.
Biopsies of the relevant nervous system tissues are generally not possible, so studies rely on post-mortem tissue.
“However, biopsies of the relevant tissues of the nervous system are generally not possible, and studies rely on post-mortem tissue.”
The paper relies on this without support.
After uptake, tau seeds need to escape the endolysosomal pathway to template aggregation of cytosolic tau.
“After uptake, tau seeds need to escape the endolysosomal pathway to template aggregation of cytosolic tau.”
The paper relies on this without support.
Nonhuman primates mirror humans more closely than mice in genome sequence, brain and circuit architecture, and have a complex behavioral and cognitive repertoire.
“Nonhuman primates mirror humans much more closely in terms of their genome sequence, brain and circuit architecture than mice do, and they possess a complex behavioral and cognitive repertoire that facilitates evaluation of phenotypes relevant to neurological disease.”
The paper relies on this without support.
Mouse models have advantages including relative ease of genetic manipulation, moderate cost, and the ability to study neuronal circuits and monitor behavioral and cognitive phenotypes.
“Mice combine several advantages, including relative ease of genetic manipulation and moderate cost, the ability to study neuronal circuits and to monitor behavioral and cognitive phenotypes.”
The paper relies on this without support.
Mouse models have provided important insights into neurological diseases and can serve as preclinical models to evaluate new therapeutic approaches.
“They have provided important insights into neurological diseases, and can serve as pre-clinical models to evaluate new therapeutic approaches.”
The paper relies on this without support.
Most academic laboratories lack the resources to perform large-scale arrayed screens.
“most academic labs do not have the resources to conduct large-scale arrayed screens.”
The paper relies on this without support.
Primary human nervous system cells are hard to obtain, and neurons are post-mitotic and cannot be expanded.
“Primary human cells of the nervous system are difficult to obtain. Neurons in particular are post-mitotic and therefore non-expandable.”
The paper relies on this without support.
Disease-associated genetic variants are being discovered rapidly, but their mechanisms are often unknown or controversial.
“Genetic variants associated with familial disease or with disease risk in sporadic patients are being identified at a rapid pace. However, the mechanism by which these variants contribute to disease is often unknown or controversial.”
The paper relies on this without support.
Many neurological disorders, especially neurodegenerative diseases, are characterized by selective vulnerability of specific cell types.
“A hallmark of many neurological disorders, in particular neurodegenerative diseases, is the selective vulnerability of specific cell types.”
The paper relies on this without support.
Genes usually act in combination with other genes rather than in isolation.
“Genes typically do not function in isolation, but in combination with other genes.”
The paper relies on this without support.
Most neurological diseases involve functional changes in specific nervous system cell types, and these functions can only be properly studied in those cell types.
“First, most neurological diseases are characterized by changes in the function of specific cell types of the nervous system, and such functions can only be appropriately studied in the relevant cell types.”
The paper relies on this without support.
Aging is the major risk factor for neurodegenerative diseases.
“aging is the major risk factor for neurodegenerative diseases.”
The paper relies on this without support.
The paper assumes that nearly all neurological disorders entail interactions among distinct cell types within a tissue environment.
“most or all neurological disorders involve interactions between different cell types in a tissue context”
The paper relies on this without support.
The paper assumes that neurological disorders appear as dysfunction of the nervous system and entail processes at the neuronal circuit level.
“neurological diseases manifest as dysfunction of the nervous system, and involve processes at the level of neuronal circuits”
The paper relies on this without support.
The paper assumes that clinical trials are presently ongoing for CRISPR-based treatments aimed at more accessible cell types, including blood cells and photoreceptor cells.
“Clinical trials are currently underway for CRISPR-based therapies targeting cells that are more easily accessible, such as blood cells and photoreceptor cells.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“we developed a CRISPRa platform in human iPSC-derived neurons to enable robust gene overexpression screens, complementing our previously established CRISPRi platform3.”
From Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis (2021) · cites this paper as [3]
In the citing paper
“We previously established a CRISPRi platform that enables robust knockdown of endogenous genes and large-scale loss-of-function genetic screens in human iPSC-derived neurons3.”
From Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis (2021) · cites this paper as [3]
In the citing paper
“We previously conducted a sub-genome scale CRISPRi screen to reveal genes controlling neuronal survival using an sgRNA library targeting 2,325 genes representing the “druggable genome”3.”
From Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis (2021) · cites this paper as [3]
In the citing paper
“Cell-type specific gene function is also supported by our recent finding that knockdown of certain genes can have remarkably different impacts on cell survival and gene expression in different isogenic human cell types, including stem cells and neurons3.”
From Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis (2021) · cites this paper as [3]
In the citing paper
“To this end, we recently developed a functional genomics platform, leveraging the strengths of CRISPR interference (CRISPRi) and induced pluripotent stem cell (iPSC) technology, that enables large-scale, multimodal loss-of-function genetic screens in differentiated human cell types, as demonstrated in neurons3.”
From Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis (2021) · cites this paper as [3]
In the citing paper
“For example, genes involved in cholesterol biosynthesis were strongly enriched in hits with toxic knockdown phenotypes, suggesting an important role of cholesterol in maintaining neuronal survival, consistent with our previous findings3.”
From Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis (2021) · cites this paper as [3]
In the citing paper
“For example, genes involved in cholesterol biosynthesis were strongly enriched in hits with toxic knockdown phenotypes, suggesting an important role of cholesterol in maintaining neuronal survival, consistent with our previous findings3.”
From Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis (2021) · cites this paper as [3]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ CRISPR-based functional genomics for neurological disease > CRISPR-based gene perturbation > Controlling gene expression
“For some genes, CRISPRi knockdown and CRISPRa knockdown will result in opposite phenotypes42.”
§ CRISPR-based functional genomics for neurological disease > CRISPR-based gene perturbation > Controlling gene expression
“Using CRISPRa, endogenous genes can be induced and overexpressed to varying degrees to evaluate functional consequences.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ CRISPR-based functional genomics for neurological disease > CRISPR screens in mammalian cells > Systematic genetic interaction screens
“Genetic modifiers for neurodegeneration have been identified successfully through human genetics, such as RAB10 for APOE65 in Alzheimer’s Disease (variants in the RAB10 locus are linked to resilience in individuals carrying the high-risk APOE ε4 allele85)”
§ CRISPR-based functional genomics for neurological disease > References
“65. Rauch JN Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs). Sci Rep 8, 6382, doi: 10.1038/s41598-018-24904-z (2018). 29686391 PMC5913225”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ CRISPR-based functional genomics for neurological disease > Applications to neurological disease > Mechanisms of disease variants
“Conceptually, the screen design is similar to screens for sensitivity to an insult (Fig. 2b) – except that the insult is the disease-associated genetic variant.”
§ CRISPR-based functional genomics for neurological disease > CRISPR screens in mammalian cells > Pooled genetic screens
“Survival-based screens can be carried out in parallel under standard culture conditions and in the presence of a toxic insult (Fig 3b).”
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Metadata
- Authors
- Kampmann, M.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Kampmann, Martin
- ORCID
- Kampmann, Martin
- Venue
- Nature Reviews Neurology
- Published
- 2020-07-08
- Volume
- 16
- Issue
- 9
- Pages
- 465-480
- ISSN
- 1759-4758 (ISSN-L)
- 1759-4766
- PMC
- PMC7484261
- OpenAlex
- W3042084835
- Cited by
- 163
- References
- 142
- Citations by year
- 2026: 24 · 2025: 32 · 2024: 29 · 2023: 21 · 2022: 28 · 2021: 26 · 2020: 3
- FWCI
- 1.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Reviews Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1r56ag057528-01a1)
- National Institute on Aging (R56 AG057528, R01AG062359)
- National Institute of Mental Health (U01MH115747)
- National Institute of General Medical Sciences (DP2GM119139)
- National Institute of Neurological Disorders and Stroke (U54NS100717)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- neurological disorders, neurodegenerative diseases, neurodevelopmental disorders, neuropsychiatric disorders, CRISPR interference, CRISPR activation, genome-wide screen, induced pluripotent stem cells, brain organoids, disease-associated variants, genetic modifier screen, therapeutic target, disease mechanisms
- MeSH terms
- Gene Editing, Animals, Humans, Nervous System Diseases, Genomics, Genome-Wide Association Study, Induced Pluripotent Stem Cells, CRISPR-Cas Systems
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