A Genomic Screen for Modifiers of Tauopathy Identifies Puromycin-Sensitive Aminopeptidase as an Inhibitor of Tau-Induced Neurodegeneration
Open accessAbstract
Neurofibrillary tangles (NFT) containing tau are a hallmark of neurodegenerative diseases, including Alzheimer's disease (AD). NFT burden correlates with cognitive decline and neurodegeneration in AD. However, little is known about mechanisms that protect against tau-induced neurodegeneration. We used a cross species functional genomic approach to analyze gene expression in multiple brain regions in mouse, in parallel with validation in Drosophila, to identify tau modifiers, including the highly conserved protein puromycin-sensitive aminopeptidase (PSA/Npepps). PSA protected against tau-induced neurodegeneration in vivo, whereas PSA loss of function exacerbated neurodegeneration. We further show that human PSA directly proteolyzes tau in vitro. These data highlight the utility of using both evolutionarily distant species for genetic screening and functional assessment to identify modifiers of neurodegeneration. Further investigation is warranted in defining the role of PSA and other genes identified here as potential therapeutic targets in tauopathy.
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Genetic loss-of-function mutations in Drosophila PSA (dPSA) enhance the tau phenotype and overexpression of dPSA suppresses the roughness.
“This approach was used to validate the in vivo protective effects of PSA, with genetic loss-of-function (LOF) mutations in Drosophila PSA (dPSA) enhancing the tau phenotype and overexpression of dPSA suppressing the roughness (48).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [48]
Genetic manipulation of PSA expression in our model was previously shown to strongly modify tau toxicity.
“Whether by cleavage or by autophagy, genetic manipulation of PSA expression in our model was previously shown in a candidate genetic approach to strongly modify tau toxicity (48).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [48]
A mouse model study of FTD identified Npepps, and cross-species analyses in flies and humans confirmed its expression pattern and neuroprotective effect.
“The first of two well-powered studies that applied this approach carried out transcriptomic analysis in a mouse model of FTD, identifying the gene Npepps138. Cross-species analyses in flies and humans confirmed the expression pattern and neuroprotective effect of NPEPPS138.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [138]
In FTD, transcriptional signatures related to differential regional vulnerability have helped identify modulators of neurodegeneration.
“In FTD, transcriptional signatures related to differential regional vulnerability have helped to identify modulators of neurodegeneration.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [138]
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- Authors
- Karsten, S. L., Sang, T.-K., Gehman, L. T., Chatterjee, S., Liu, J., Lawless, G. M., Sengupta, S., Berry, R. W., Pomakian, J., Oh, H. S., Schulz, C., Hui, K.-S., Wiedau-Pazos, M., Vinters, H. V., Binder, L. I., Geschwind, D. H., & Jackson, G. R.
- Affiliations
- University of California, Los Angeles (US)
- Northwestern University (US)
- Kyungwoon University (KR)
- Cold Spring Harbor Laboratory (US)
- Nathan Kline Institute for Psychiatric Research (US)
- Corresponding author
- Geschwind, Daniel H.
- Jackson, George R.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2006-09
- Volume
- 51
- Issue
- 5
- Pages
- 549-560
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2041544905
- Cited by
- 147
- References
- 69
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 7 · 2023: 6 · 2022: 2 · 2021: 8 · 2020: 3 · 2019: 4 · 2018: 11 · 2017: 5 · 2016: 1 · 2015: 5 · 2014: 7 · 2013: 8 · 2012: 10
- FWCI
- 7.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2511 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- Alzheimer's Disease Research Foundation
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tauopathy, neurofibrillary tangles, puromycin-sensitive aminopeptidase, Alzheimer's disease, Drosophila, mice, therapeutic target
- MeSH terms
- Aminopeptidases, Animals, Brain, Drosophila, Humans, Immunohistochemistry, Mice, Transgenic, Nerve Degeneration, Blotting, Northern, Blotting, Western, Neurofibrillary Tangles, tau Proteins, In Situ Hybridization, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Tauopathies, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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