Evidence map›Paper›PMID 37034684›Full record

ArticlebioRxiv : the preprint server for biology2025

Proteostasis and lysosomal repair deficits in transdifferentiated neurons of Alzheimer's disease.

Ching-Chieh Chou, Ryan Vest, Miguel A Prado, Joshua Wilson-Grady, Joao A Paulo, Yohei Shibuya, Patricia Moran-Losada, Ting-Ting Lee, Jian Luo, Steven P Gygi and 5 more

Open access · greenAbstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed, 16 citations in OpenAlex.

  1. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

15 authors at 5 institutions in 2 countries.

Ching-Chieh ChouDepartment of Biology, Stanford University, Stanford, California, USA.ORCID 0000-0001-8302-2915
Ryan VestDepartment of Chemical Engineering, Stanford University, Stanford, California, USA.
Miguel A PradoDepartment of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Joshua Wilson-GradyDepartment of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Joao A PauloDepartment of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.ORCID 0000-0002-4291-413X
Yohei ShibuyaDepartments of Pathology, Stanford University School of Medicine, Stanford, California, USA.
Patricia Moran-LosadaWu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, California, USA.
Ting-Ting LeeDepartment of Biology, Stanford University, Stanford, California, USA.
Jian LuoPalo Alto Veterans Institute for Research, Inc. (PAVIR), Palo Alto, California, USA.
Steven P GygiDepartment of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Jeffery W KellyDepartment of Chemistry, The Scripps Research Institute, La Jolla, California, USA.
Daniel FinleyDepartment of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Marius WernigDepartments of Pathology, Stanford University School of Medicine, Stanford, California, USA.
Tony Wyss-CorayWu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, California, USA.ORCID 0000-0001-5893-0831
Judith FrydmanDepartment of Biology, Stanford University, Stanford, California, USA.ORCID 0000-0003-2302-6943
Harvard University · USStanford University · USNeurosciences Institute · USPalo Alto Veterans Institute for Research · USScripps Research Institute · US

Funding

Stanford Alzheimer's Disease Research CenterAdmin Supp: Developing iPSC models for AD and PDP30AG066515 · NIA · STANFORD UNIVERSITY · PI Lisa Goldman Rosas · 2020 to 2026
$29.0M
The proteasome in aging and neurodegenerative diseaseP01AG054407 · NIA · NORTHWESTERN UNIVERSITY · PI FINLEY, DANIEL J · 2018 to 2022
$14.0M
Working Memory in Parkinson Disease: A Cognitive & Systems Neuroscience ApproachP50AG047366 · NIA · STANFORD UNIVERSITY · PI HENDERSON, VICTOR · 2015 to 2019
$7.9M
Advancing Multiplexed Isobaric Tag-based Strategies for Proteome ProfilingR01GM132129 · NIGMS · HARVARD MEDICAL SCHOOL · PI PAULO, JOAO A · 2019 to 2023
$1.7M
NIA NIH HHS P01 AG054407NIA NIH HHS P30 AG066515NIA NIH HHS P50 AG047366NIGMS NIH HHS R01 GM132129
6 · The paper itself

Abstract

Aging 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 AD brains remain elusive. Here, we develop transdifferentiated neurons (tNeurons) from human dermal fibroblasts as a neuronal model that retains aging hallmarks and exhibits AD-linked vulnerabilities. Remarkably, AD tNeurons accumulate proteotoxic deposits, including phospho-Tau and Aβ, resembling those in AD patient and APP mouse brains. Quantitative tNeuron proteomics identify aging 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. Supporting lysosomal deficits' centrality in AD, compounds ameliorating lysosomal function reduce Aβ deposits and cytokine secretion. Thus, the tNeuron model system reveals impaired lysosomal homeostasis as an early event of aging and AD.

Identifiers

PMID37034684
PMCPMC10081252
OpenAlexW4361215982

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.