ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2024
Person-specific differences in ubiquitin-proteasome mediated proteostasis in human neurons.
Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 20 citations in OpenAlex.
- Human iPSC models revealResearch square · 2026Article
- Composition and activity of the proteasome in human iPSC-derived neuronal model of early-stage sporadic Alzheimer's disease.bioRxiv : the preprint server for biology · 2026Article
- The emerging role of ubiquitin-proteasome system dysfunction in the pathogenesis of perioperative neurocognitive disorders: a narrative review.Frontiers in behavioral neuroscience · 2026Review
- Human clearance systems have a layered architecture across tissues and cell types that supports varied proteome compositions.Autophagy · 2026Article
- POU3F2 regulates canonical Wnt signalling via SOX13 and ADNP to expand the neural progenitor population.Brain : a journal of neurology · 2025Article
- Early proteasome downregulation and dysfunction drive proteostasis failure in Alzheimer's disease.Brain : a journal of neurology · 2025Article
- Repeated Exposure to Lidocaine Induces Alzheimer's‐Like Cognitive Impairment and Neuropathology in Aged Mice Through BDNF‐Regulated Autophagy.Journal of cellular and molecular medicine · 2025Article
- The Proteostasis Network in Proteinopathies: Mechanisms and Interconnections.The American journal of pathology · 2025Review
- Proteomic Insight Into Alzheimer's Disease Pathogenesis Pathways.Proteomics · 2025Review
- Genetic and proteomic analysis identifies BAG3 as an amyloid-responsive regulator of neuronal proteostasis.Acta neuropathologica · 2025Article
- Adaptive Suppression of MAPT Transcription Maintains Tau Proteostasis in Developing Human Neurons.Research square · 2025Article
- Optineurin deficiency disrupts phosphorylated tau proteostasis and clusterin expression in human neurons.Acta neuropathologica communications · 2025Article
- Article
- Translating the Post-Mortem Brain Multi-Omics Molecular Taxonomy of Alzheimer's Dementia to Living Humans.bioRxiv : the preprint server for biology · 2025Article
- Redox regulation: mechanisms, biology and therapeutic targets in diseases.Signal transduction and targeted therapy · 2025Review
- Transcriptomic comparison of corneal endothelial cells in young versus old corneas.Scientific reports · 2024Article
- NF-κB in Alzheimer's Disease: Friend or Foe? Opposite Functions in Neurons and Glial Cells.International journal of molecular sciences · 2024Review
- Person-specific differences in ubiquitin-proteasome mediated proteostasis in human neurons.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
Corrections and comments
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Authors and funding
13 authors at 7 institutions in 2 countries.
Funding
Abstract
backgroundImpairment of the ubiquitin-proteasome system (UPS) has been implicated in abnormal protein accumulation in Alzheimer's disease. It remains unclear if genetic variation affects the intrinsic properties of neurons that render some individuals more vulnerable to UPS impairment.
methodsInduced pluripotent stem cell (iPSC)-derived neurons were generated from over 50 genetically variant and highly characterized participants of cohorts of aging. Proteomic profiling, proteasome activity assays, and Western blotting were employed to examine neurons at baseline and in response to UPS perturbation.
resultsNeurons with lower basal UPS activity were more vulnerable to tau accumulation following mild UPS inhibition. Chronic reduction in proteasome activity in human neurons induced compensatory elevation of regulatory proteins involved in proteostasis and several proteasome subunits. DISCUSSION: These findings reveal that genetic variation influences basal UPS activity in human neurons and differentially sensitizes them to external factors perturbing the UPS, leading to the accumulation of aggregation-prone proteins such as tau. HIGHLIGHTS: Polygenic risk score for AD is associated with the ubiquitin-proteasome system (UPS) in neurons. Basal proteasome activity correlates with aggregation-prone protein levels in neurons. Genetic variation affects the response to proteasome inhibition in neurons. Neuronal proteasome perturbation induces an elevation in specific proteins involved in proteostasis. Low basal proteasome activity leads to enhanced tau accumulation with UPS challenge.
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Registered trials
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.