Person-specific differences in ubiquitin-proteasome mediated proteostasis in human neurons.
Alzheimers Dement
; 20(4): 2952-2967, 2024 04.
Article
em En
| MEDLINE
| ID: mdl-38470006
ABSTRACT
BACKGROUND:
Impairment 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.METHODS:
Induced 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.RESULTS:
Neurons 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.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ubiquitina
/
Complexo de Endopeptidases do Proteassoma
Limite:
Humans
Idioma:
En
Revista:
Alzheimers Dement
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos