Linking tuberous sclerosis complex, excessive mTOR signaling, and age-related neurodegeneration: a new association between TSC1 mutation and frontotemporal dementia
Open accessAbstract
Author(s): Olney, Nicholas T; Alquezar, Carolina; Ramos, Eliana Marisa; Nana, Alissa L; Fong, Jamie C; Karydas, Anna M; Taylor, Joanne B; Stephens, Melanie L; Argouarch, Andrea R; Van Berlo, Victoria A; Dokuru, Deepika R; Sherr, Elliott H; Jicha, Gregory A; Dillon, William P; Desikan, Rahul S; De May, Mary; Seeley, William W; Coppola, Giovanni; Miller, Bruce L; Kao, Aimee W
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Prior reports depict tau-related changes as elevated p-tau staining in the absence of frank neurofibrillary tangles.
“Generally, prior reports depict tau-related changes as elevated p-tau staining in the absence of frank neurofibrillary tangles.”
From Tuberous sclerosis complex is associated with a novel human tauopathy (2023) · cites this paper as [16]
In the paper’s neuropathology account (page unavailable), the affected sibling’s tissue showed phosphorylated-tau staining, and no neurofibrillary tangles were observed. This supports the described pattern in this case, but the case report does not establish that prior reports generally show the same pattern. (LLM, conf=0.86)
Experimental — accuracy not yet measuredA novel genetic variant in the TSC1 gene represents a potential cause of FTLD-tau.
“In 2017,21 we described a novel genetic variant in the TSC1 gene that represents a potential cause of FTLD-tau, and a deregulation in hamartin, the protein product of TSC1, which is an important upstream modifier of mammalian target of rapamycin (mTOR) activity.”
From Association of Cognitive and Behavioral Features Between Adults With Tuberous Sclerosis and Frontotemporal Dementia (2020) · cites this paper as [21]
The case report (page unavailable) identifies a novel TSC1 frameshift variant in a patient with probable bvFTD and suggests that TSC1-related tau accumulation may contribute to neurodegeneration. It does not establish the more specific FTLD-tau classification: the sibling’s tissue showed phosphorylated tau but lacked the characteristic features of an inherited or sporadic tauopathy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredA TSC1 mutation carrier presented with a progressive neurodegenerative syndrome that met clinical research criteria for behavioral variant frontotemporal dementia and showed prominent right anterior temporal lobe atrophy.
“Recently, we reported a TSC1 mutation carrier who presented with a progressive neurodegenerative syndrome that met clinical research criteria for behavioral variant frontotemporal dementia (bvFTD) and showed prominent right anterior temporal lobe atrophy [16].”
From Tuberous sclerosis complex is associated with a novel human tauopathy (2023) · cites this paper as [16]
Frontal lobe tissue surgically resected from the patient's sibling showed elevated tau phosphorylation without evidence of tau aggregation or tangle formation.
“Frontal lobe tissue surgically resected for treatment of TSC-related epilepsy from the patient’s living sibling showed elevated tau phosphorylation without evidence of tau aggregation or tangle formation [16].”
From Tuberous sclerosis complex is associated with a novel human tauopathy (2023) · cites this paper as [16]
TSC tauopathy differs from other TSC-related tau abnormalities previously reported.
“TSC tauopathy also differs from other TSC-related tau abnormalities previously reported in the TSC literature by our group [12, 16] and others [6, 11].”
From Tuberous sclerosis complex is associated with a novel human tauopathy (2023) · cites this paper as [16]
TSC has been linked to progressive neurodegeneration and FTD-like symptoms.
“TSC has been linked to progressive neurodegeneration and FTD-like symptoms [12, 16].”
From Tuberous sclerosis complex is associated with a novel human tauopathy (2023) · cites this paper as [16]
Serpins and cystatins can act as endogenous protease inhibitors.
“Further, other lysosomal proteins, such as serpins and cystatins, can act as endogenous protease inhibitors.121”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [121]
The paper’s discussion of TSC1, mTOR activity, and protein degradation does not address whether serpins or cystatins act as endogenous protease inhibitors. Searches of our copy for those proteins and for lysosomal protease inhibitors found no passage addressing the claim. (LLM, conf=0.75)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Tuberous Sclerosis Associated Neuropsychiatric Disorders (TAND) and the TAND Checklist
de Vries, P. J., Whittemore, V. H., Leclezio, L., Byars, A. W., Dunn, D., Ess, K. C., Hook, D., King, B. H., Sahin, M., & Jansen, A. (2015) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2014.10.004 · Cited by 371 · see citing works
Flagged first, then by citations
Research works printed but not linked: 15
- [1]Caccamo A Magri A Medina DX Wisely EV Lopez-Aranda MF Silva AJ Oddo S mTOR regulates tau phosphorylation and degradation: implications for Alzheimer’s disease and other tauopathies Aging Cell 2013 12 370 380 10.1111/acel.12057 23425014 PMC3655115 · DOI · Paper page
- [2]Cairns NJ Bigio EH Mackenzie IR Neumann M Lee VM Hatanpaa KJ White CL 3rd Schneider JA Grinberg LT Halliday G Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration Acta Neuropathol (Berl) 2007 114 5 22 10.1007/s00401-007-0237-2 17579875 PMC2827877 · DOI · Paper page
- [3]Crino PB The mTOR signalling cascade: paving new roads to cure neurological disease Nat Rev Neurol 2016 12 379 392 10.1038/nrneurol.2016.81 27340022 · DOI · Paper page
- [4]Curatolo P Moavero R de Vries PJ Neurological and neuropsychiatric aspects of tuberous sclerosis complex Lancet Neurol 2015 14 733 745 10.1016/S1474-4422(15)00069-1 26067126 · DOI · Paper page
- [6]Doudna JA Charpentier E Genome editing. The new frontier of genome engineering with CRISPR-Cas9 Science 2014 346 1258096 10.1126/science.1258096 25430774 · DOI · Paper page
- [7]Encinas M Iglesias M Liu Y Wang H Muhaisen A Cena V Gallego C Comella JX Sequential treatment of SH-SY5Y cells with retinoic acid and brain-derived neurotrophic factor gives rise to fully differentiated, neurotrophic factor-dependent, human neuron-like cells J Neurochem 2000 75 991 1003 10.1046/j.1471-4159.2000.0750991.x 10936180 · DOI
- [8]Laplante M Sabatini DM mTOR signaling in growth control and disease Cell 2012 149 274 293 10.1016/j.cell.2012.03.017 22500797 PMC3331679 · DOI · Paper page
- [9]Lipton JO Sahin M The neurology of mTOR Neuron 2014 84 275 291 10.1016/j.neuron.2014.09.034 25374355 PMC4223653 · DOI
- [10]Nixon RA The role of autophagy in neurodegenerative disease Nat Med 2013 19 983 997 10.1038/nm.3232 23921753 · DOI · Paper page
- [11]Qin W Chan JA Vinters HV Mathern GW Franz DN Taillon BE Bouffard P Kwiatkowski DJ Analysis of TSC cortical tubers by deep sequencing of TSC1, TSC2 and KRAS demonstrates that small second-hit mutations in these genes are rare events Brain Pathol 2010 20 1096 1105 10.1111/j.1750-3639.2010.00416.x 20633017 PMC2951479 · DOI
- [12]Rascovsky K Hodges JR Knopman D Mendez MF Kramer JH Neuhaus J van Swieten JC Seelaar H Dopper EG Onyike CU Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia Brain 2011 134 2456 2477 10.1093/brain/awr179 21810890 PMC3170532 · DOI · Paper page
- [13]Sarnat HB Flores-Sarnat L Infantile tauopathies: hemimegalencephaly; tuberous sclerosis complex; focal cortical dysplasia 2; ganglioglioma Brain Dev 2015 37 553 562 10.1016/j.braindev.2014.08.010 25451314 · DOI · Paper page
- [14]Siman R Cocca R Dong Y The mTOR inhibitor rapamycin mitigates perforant pathway neurodegeneration and synapse loss in a mouse model of early-stage alzheimer-type tauopathy PLoS ONE 2015 10 e0142340 10.1371/journal.pone.0142340 26540269 PMC4634963 · DOI
- [15]Smith KR Damiano J Franceschetti S Carpenter S Canafoglia L Morbin M Rossi G Pareyson D Mole SE Staropoli JF Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage Am J Hum Genet 2012 90 1102 1107 10.1016/j.ajhg.2012.04.021 22608501 PMC3370276 · DOI · Paper page
- [16]Tang Z Ioja E Bereczki E Hultenby K Li C Guan Z Winblad B Pei JJ mTor mediates tau localization and secretion: implication for Alzheimer’s disease Biochim Biophys Acta 2015 1853 1646 1657 10.1016/j.bbamcr.2015.03.003 25791428 · DOI · Paper page
Cited by
Sorted by citations
Alquezar, C., Schoch, K. M., Geier, E. G., Ramos, E. M., Scrivo, A., Li, K. H., Argouarch, A. R., Mlynarski, E. E., Dombroski, B., DeTure, M., et al. (2021) · Science Advances · doi:10.1126/sciadv.abg3897 · Cited by 56 · see citing works
Self-citationLiu, A. J., Staffaroni, A. M., Rojas-Martinez, J. C., Olney, N. T., Alquezar-Burillo, C., Ljubenkov, P. A., La Joie, R., Fong, J. C., Taylor, J., Karydas, A., et al. (2020) · JAMA Neurology · doi:10.1001/jamaneurol.2019.4284 · Cited by 18 · see citing works
Self-citationLiu, A. J., Lusk, J. B., Ervin, J., Burke, J., O’Brien, R., & Wang, S.-H. J. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01330-x · Cited by 15 · see citing works
Tuberous sclerosis complex is associated with a novel human tauopathy
Hwang, J.-H. L., Perloff, O. S., Gaus, S. E., Benitez, C., Alquezar, C., Cosme, C. Q., Nana, A. L., Vatsavayai, S. C., Ramos, E. M., Geschwind, D. H., et al. (2023) · Acta Neuropathologica · doi:10.1007/s00401-022-02521-5 · Cited by 15 · see citing works
“TSC tauopathy represents a primary tauopathy, and TSC has been linked to progressive neurodegeneration and FTD-like symptoms [12, 16].”
BackgroundMethodInfluentialSelf-citationLane-Donovan, C., Paredes, M., & Kao, A. W. (2025) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2025.102854 · Cited by 3 · see citing works
Self-citation
- Authors
- Olney, N. T., Alquezar, C., Ramos, E. M., Nana, A. L., Fong, J. C., Karydas, A. M., Taylor, J. B., Stephens, M. L., Argouarch, A. R., Van Berlo, V. A., Dokuru, D. R., Sherr, E. H., Jicha, G. A., Dillon, W. P., Desikan, R. S., De May, M., Seeley, W. W., Coppola, G., Miller, B. L., & Kao, A. W.
- Affiliations
- University of California, San Francisco (US)
- University of California, Los Angeles (US)
- University of Kentucky (US)
- Corresponding author
- Kao, Aimee W.
- ORCID
- Venue
- Acta Neuropathologica
- Published
- 2017-08-21
- Volume
- 134
- Issue
- 5
- Pages
- 813-816
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC5645431
- OpenAlex
- W2745991302
- Cited by
- 15
- References
- 1
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2022: 3 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 2
- FWCI
- 1.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- UKnowledge (University of Kentucky) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Rainwater Tau Consortium
- NIH/NIA (P50AG023501)
- National Institute on Aging (P01AG019724, P50 AG1657303, RC1 AG035610)
- National Institutes of Health (T32AG023481-11S1, U24DA041123)
- Fundación Ramón Areces
- Paul G. Allen Family Foundation
- John Douglas French Alzheimer's Foundation
- National Alzheimer's Coordinating Center Junior Investigator Award
- ASNR Alzheimer's Imaging Research Grant Program
- RSNA Resident Fellow grant
- Topics
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tuberous sclerosis complex, TSC1 mutation, mTOR signaling, frontotemporal dementia, age-related neurodegeneration, genetic association, neurodegeneration
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Humans, Male, Middle Aged, Mutation, Tuberous Sclerosis, Signal Transduction, Tumor Suppressor Proteins, Frontotemporal Dementia, TOR Serine-Threonine Kinases
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 ›
Are you an author, or do you see a problem with this page? Request a review
