Genetic and proteomic analysis identifies BAG3 as an amyloid-responsive regulator of neuronal proteostasis

Oct 14, 2025Acta neuropathologica

Genetic and protein studies identify BAG3 as a regulator that responds to amyloid and controls protein balance in neurons

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Abstract

Substantial inter-individual differences in were observed among neurons derived from a large panel of iPSCs.

Autophagic flux was found to be inversely correlated with ubiquitin-proteasome system activity.
Higher autophagic flux was associated with reduced accumulation of aggregated, phosphorylated tau.
Global protein turnover dynamics varied based on the activity of degradation pathways and predicted substrate dependencies.
was identified as a dynamically regulated chaperone that influences autophagic flux in neurons.
Knockout of BAG3 in neurons led to decreased autophagic flux and increased levels of high-molecular-weight phosphorylated tau.
Familial Alzheimer's disease mutations and Aβ exposure were linked to increased BAG3 expression in neurons.

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The autophagy-lysosome pathway (ALP) and the ubiquitin-proteasome system (UPS) are the primary protein degradative mechanisms maintaining proteostasis in neurons. However, the impact of human genetic variation on these pathways and the role of are poorly understood, particularly in the context of Alzheimer's disease, where proteostatic dysfunction is a defining hallmark. We utilized a large panel of iPSCs from deeply phenotyped cohorts to interrogate genetic contributions to baseline and UPS activity in human neurons, and protein turnover was assessed using SILAC-based quantitative proteomics. Across this panel of neurons, we observed substantial inter-individual differences in autophagic flux, which was inversely correlated with UPS activity. This reciprocal relationship extended to tau homeostasis, where higher autophagic flux resulted in reduced accumulation of aggregated, phosphorylated tau. Proteomic analyses revealed that global protein turnover dynamics stratified based on degradation pathway activity and could predict pathway-specific substrate dependencies. Interestingly, Bcl-2-associated athanogene 3 (BAG3), an important member of the chaperone-assisted selective autophagy pathway, emerged as a dynamically regulated autophagy chaperone, responsive to pharmacological inhibition of both the UPS and ALP. BAG3 knockout in neurons decreased autophagic flux and increased levels of high-molecular-weight phosphorylated tau. Notably, familial AD mutations and Aβ exposure induced BAG3 expression in neurons, while elevated BAG3 levels in human brain tissue were associated with higher neuropathological burden and disease progression. Our findings identify BAG3 as a key modulator of proteostasis in human neurons. Its regulation across genetic backgrounds and pathological stimuli suggests a central role in maintaining degradation activities in Alzheimer's disease and related disorders.

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Genetic and proteomic analysis identifies BAG3 as an amyloid-responsive regulator of neuronal proteostasis

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