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[Preprint]. 2024 May 30:rs.3.rs-4407236.

doi: 10.21203/rs.3.rs-4407236/v1.

Human tNeurons reveal aging-linked proteostasis deficits driving Alzheimer's phenotypes

Ching-Chieh Chou¹, Ryan Vest^{2

3

4}, Miguel A Prado^{5

6}, Joshua Wilson-Grady⁵, Joao A Paulo⁵, Yohei Shibuya^{7

8}, Patricia Moran-Losada^{9

3}, Ting-Ting Lee¹, Jian Luo¹⁰, Steven P Gygi⁵, Jeffery W Kelly^{11

12}, Daniel Finley⁵, Marius Wernig^{7

8}, Tony Wyss-Coray^{9

3}, Judith Frydman^{1

13

9

14

15}

Affiliations

¹ Department of Biology, Stanford University, Stanford, California, USA.
² Department of Chemical Engineering, Stanford University, Stanford, California, USA.
³ Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA.
⁴ Qinotto, Inc. San Carlos, California, USA.
⁵ Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
⁶ Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
⁷ Departments of Pathology, Stanford University School of Medicine, Stanford, California, USA.
⁸ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
⁹ Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, California, USA.
¹⁰ Palo Alto Veterans Institute for Research, Inc. (PAVIR), Palo Alto, California, USA.
¹¹ Department of Chemistry, The Scripps Research Institute, La Jolla, California, USA.
¹² The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
¹³ Department of Genetics, Stanford University, Stanford, California, USA.
¹⁴ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
¹⁵ Lead contact.

PMID: 38853828
PMCID: PMC11160905
DOI: 10.21203/rs.3.rs-4407236/v1

Human tNeurons reveal aging-linked proteostasis deficits driving Alzheimer's phenotypes

Ching-Chieh Chou et al. Res Sq. 2024.

[Preprint]. 2024 May 30:rs.3.rs-4407236.

doi: 10.21203/rs.3.rs-4407236/v1.

Authors

Affiliations

¹ Department of Biology, Stanford University, Stanford, California, USA.
² Department of Chemical Engineering, Stanford University, Stanford, California, USA.
³ Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA.
⁴ Qinotto, Inc. San Carlos, California, USA.
⁵ Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
⁶ Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
⁷ Departments of Pathology, Stanford University School of Medicine, Stanford, California, USA.
⁸ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
⁹ Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, California, USA.
¹⁰ Palo Alto Veterans Institute for Research, Inc. (PAVIR), Palo Alto, California, USA.
¹¹ Department of Chemistry, The Scripps Research Institute, La Jolla, California, USA.
¹² The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
¹³ Department of Genetics, Stanford University, Stanford, California, USA.
¹⁴ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
¹⁵ Lead contact.

PMID: 38853828
PMCID: PMC11160905
DOI: 10.21203/rs.3.rs-4407236/v1

Update in

Proteostasis and lysosomal repair deficits in transdifferentiated neurons of Alzheimer's disease.
Chou CC, Vest R, Prado MA, Wilson-Grady J, Paulo JA, Shibuya Y, Moran-Losada P, Lee TT, Luo J, Gygi SP, Kelly JW, Finley D, Wernig M, Wyss-Coray T, Frydman J. Chou CC, et al. Nat Cell Biol. 2025 Apr;27(4):619-632. doi: 10.1038/s41556-025-01623-y. Epub 2025 Mar 26. Nat Cell Biol. 2025. PMID: 40140603 Free PMC article.

Abstract

Aging is a prominent risk factor for Alzheimer's disease (AD), but the cellular mechanisms underlying neuronal phenotypes remain elusive. Both accumulation of amyloid plaques and neurofibrillary tangles in the brain¹ and age-linked organelle deficits^2-7 are proposed as causes of AD phenotypes but the relationship between these events is unclear. Here, we address this question using a transdifferentiated neuron (tNeuron) model directly from human dermal fibroblasts. Patient-derived tNeurons retain aging hallmarks and exhibit AD-linked deficits. Quantitative tNeuron proteomic analyses identify aging and AD-linked deficits in proteostasis and organelle homeostasis, particularly affecting endosome-lysosomal components. The proteostasis and lysosomal homeostasis deficits in aged tNeurons are exacerbated in sporadic and familial AD tNeurons, promoting constitutive lysosomal damage and defects in ESCRT-mediated repair. We find deficits in neuronal lysosomal homeostasis lead to inflammatory cytokine secretion, cell death and spontaneous development of Aß and phospho-Tau deposits. These proteotoxic inclusions co-localize with lysosomes and damage markers and resemble inclusions in brain tissue from AD patients and APP-transgenic mice. Supporting the centrality of lysosomal deficits driving AD phenotypes, lysosome-function enhancing compounds reduce AD-associated cytokine secretion and Aβ deposits. We conclude that proteostasis and organelle deficits are upstream initiating factors leading to neuronal aging and AD phenotypes.

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Conflict of interest statement

Competing interests: R.V., J.L. and T.W.-C. are co-founders of Qinotto Inc.

References

1. Ross C. A. & Poirier M. A. Protein aggregation and neurodegenerative disease. Nature medicine 10 Suppl, S10–17 (2004). 10.1038/nm1066 - DOI - PubMed
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1. Gottschling D. E. & Nyström T. The Upsides and Downsides of Organelle Interconnectivity. Cell 169, 24–34 (2017). 10.1016/j.cell.2017.02.030 - DOI - PMC - PubMed

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This is a preprint.

Human tNeurons reveal aging-linked proteostasis deficits driving Alzheimer's phenotypes

Affiliations

Human tNeurons reveal aging-linked proteostasis deficits driving Alzheimer's phenotypes

Authors

Affiliations

Update in

Abstract

Conflict of interest statement

References

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