Person‐specific differences in ubiquitin‐proteasome mediated proteostasis in human neurons

Author:

Hsieh Yi‐Chen1,Augur Zachary M.1,Arbery Mason1,Ashour Nancy1,Barrett Katharine1,Pearse Richard V.1,Tio Earvin S.2,Duong Duc M.3,Felsky Daniel24,De Jager Philip L.5,Bennett David A.6,Seyfried Nicholas T.37,Young‐Pearse Tracy L.18

Affiliation:

1. Ann Romney Center for Neurologic Diseases Department of Neurology Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts USA

2. Department of Psychiatry and Institute of Medical Science University of Toronto Toronto Ontario Canada

3. Department of Biochemistry Emory University School of Medicine Atlanta Georgia USA

4. Krembil Centre for Neuroinformatics Centre for Addiction and Mental Health Toronto Ontario Canada

5. Center for Translational and Computational Neuroimmunology Department of Neurology and the Taub Institute for the Study of Alzheimer's Disease and the Aging Brain Columbia University Irving Medical Center New York New York USA

6. Rush Alzheimer's Disease Center Rush University Medical Center Chicago Illinois USA

7. Department of Neurology Emory University School of Medicine Atlanta Georgia USA

8. Harvard Stem Cell Institute Harvard University Cambridge Massachusetts USA

Abstract

AbstractBACKGROUNDImpairment 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.DISCUSSIONThese 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.

Funder

National Institutes of Health

Publisher

Wiley

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