The DOI matches its Crossref record; 112 of the 112 references it cites were found in a registry or an index.
Proteostasis and lysosomal repair deficits in transdifferentiated neurons of Alzheimer’s disease
Open accessPublished version of a preprint
Abstract
Ageing is the most prominent risk factor for Alzheimer’s disease (AD). However, the cellular mechanisms linking neuronal proteostasis decline to the characteristic aberrant protein deposits in the brains of patients with AD remain elusive. Here we develop transdifferentiated neurons (tNeurons) from human dermal fibroblasts as a neuronal model that retains ageing hallmarks and exhibits AD-linked vulnerabilities. Remarkably, AD tNeurons accumulate proteotoxic deposits, including phospho-tau and amyloid β, resembling those in APP mouse brains and the brains of patients with AD. Quantitative tNeuron proteomics identify ageing- and AD-linked deficits in proteostasis and organelle homeostasis, most notably in endosome–lysosomal components. Lysosomal deficits in aged tNeurons, including constitutive lysosomal damage and ESCRT-mediated lysosomal repair defects, are exacerbated in AD tNeurons and linked to inflammatory cytokine secretion and cell death. Providing support for the centrality of lysosomal deficits in AD, compounds ameliorating lysosomal function reduce amyloid β deposits and cytokine secretion. Thus, the tNeuron model system reveals impaired lysosomal homeostasis as an early event of ageing and AD.
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“their enzymatic substrate, PI(3,4,5)P3, can induce lysosome de-acidification by activating the lysosomal potassium channel TMEM17567.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [67]
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“Even beyond early embryonic development, the number and morphology of dendritic spines remain dynamic and are ultimately distorted in disease.30,31”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [31]
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Mechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases
Nixon, R. A., & Rubinsztein, D. C. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00757-5 · Cited by 435
Tau fibrils induce nanoscale membrane damage and nucleate cytosolic tau at lysosomes
Rose, K. M., Jepson, T. A., Shukla, S., Maya-Romero, A., Kampmann, M., Xu, K., & Hurley, J. H. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2315690121 · Cited by 81
The expanding repertoire of ESCRT functions in cell biology and disease
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Proteostasis disruption and senescence in Alzheimer’s disease pathways to neurodegeneration
Thapa, R., Bhat, A. A., Shahwan, M. J., Ali, H., Padmapriya, G., Bansal, P., Rajotiya, S., Barwal, A., Prasad, G. V. S., Pramanik, A., et al. (2024) · Brain Research · doi:10.1016/j.brainres.2024.149202 · Cited by 48
Neuronal constitutive endolysosomal perforations enable α-synuclein aggregation by internalized PFFs
Sanyal, A., Scanavachi, G., Somerville, E., Saminathan, A., Nair, A., Correia, R. F. B. D. C., Aylan, B., Sitarska, E., Oikonomou, A., Hatzakis, N. S., et al. (2024) · The Journal of Cell Biology · doi:10.1083/jcb.202401136 · Cited by 26
Metadata
- Authors
- Chou, C.-C., Vest, R., Prado, M. A., Wilson-Grady, J., Paulo, J. A., Shibuya, Y., Moran-Losada, P., Lee, T.-T., Luo, J., Gygi, S. P., Kelly, J. W., Finley, D., Wernig, M., Wyss-Coray, T., & Frydman, J.
- Affiliations
- Aligning Science Across Parkinson's (US)
- Stanford University (US)
- Harvard University (US)
- Stanford Medicine (US)
- Palo Alto Veterans Institute for Research (US)
- Scripps Research Institute (US)
- Corresponding author
- Chou, Ching-Chieh
- Frydman, Judith
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2025-03-26
- Volume
- 27
- Issue
- 4
- Pages
- 619-632
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC11991917
- OpenAlex
- W4408873575
- Cited by
- 94
- References
- 111
- Citations by year
- 2026: 58 · 2025: 23
- FWCI
- 52.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Cell Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- Funders
- Michael J. Fox Foundation for Parkinson's Research (ASAP-000282)
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (AG054407)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- Alzheimer's disease, neuronal proteostasis, fibroblast-to-neuron conversion, aging, amyloid-beta, tau phosphorylation, ESCRT, inflammatory cytokines, cell death, proteomics, lysosomal dysfunction
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