Proteostasis and lysosomal repair deficits in transdifferentiated neurons of Alzheimer’s disease
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.
Authors
- Ching‐Chieh Chou (ORCID: https://orcid.org/0000-0001-8302-2915)
- Yohei Shibuya (ORCID: https://orcid.org/0000-0002-8825-5440)
- Miguel A. Prado (ORCID: https://orcid.org/0000-0002-4914-1619)
- João A. Paulo (ORCID: https://orcid.org/0000-0002-4291-413X)
- Tony Wyss‐Coray (ORCID: https://orcid.org/0000-0001-5893-0831)
- Judith Frydman (ORCID: https://orcid.org/0000-0003-2302-6943)
- Ryan T. Vest
- Joshua Wilson‐Grady (ORCID: https://orcid.org/0000-0001-6919-0410)
- Jian Luo (ORCID: https://orcid.org/0000-0002-2064-8467)
- Ting-Ting Lee (ORCID: https://orcid.org/0000-0003-1010-3292)
- Steven P. Gygi (ORCID: https://orcid.org/0000-0001-7626-0034)
- Marius Wernig (ORCID: https://orcid.org/0000-0002-5309-515X)
- Jeffery W. Kelly (ORCID: https://orcid.org/0000-0001-8943-3395)
- Daniel Finley (ORCID: https://orcid.org/0000-0003-2076-5863)
- Patricia Moran‐Losada
Institutions
- Scripps Research Institute (US)
- Harvard University (US)
- Neurosciences Institute (US)
- Palo Alto Veterans Institute for Research (US)
- Research Network (United States) (US)
- Instituto de Investigación Sanitaria del Principado de Asturias (ES)
- Stanford University (US)
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2025-03-26
- DOI
- https://doi.org/10.1038/s41556-025-01623-y
- Citations
- 33
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 38.42
Funders
- Michael J. Fox Foundation for Parkinson's Research
- National Institute on Aging