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Genetic and proteomic analysis identifies BAG3 as an amyloid-responsive regulator of neuronal proteostasis
Zachary M Augur, Garrett M Fogo, Mason R Arbery, Yi-Chen Hsieh, Nalini R Rao, Kritika Goyal, Emily Dexter, David A Bennett et al.. Acta neuropathologica, 2025-10-14
Topic: Disease mechanisms in lab and animal studies
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 BAG3 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 autophagic flux 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.
Key findings
- Across this panel of neurons, we observed substantial inter-individual differences in autophagic flux, which was inversely correlated with UPS activity.
- Proteomic analyses revealed that global protein turnover dynamics stratified based on degradation pathway activity and could predict pathway-specific substrate dependencies.
- 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.
Study details
- Evidence strengthLow
How this study scored 46/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 26 of the 56 points we could judge it on, which is 46 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Acta neuropathologica) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41085772) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 26 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 26 of the 56 points we could judge it on is 46 out of 100. |
| Total | 46 / 100 | — |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Augur, Z. M., Fogo, G. M., Arbery, M. R., Hsieh, Y.-C., Rao, N. R., Goyal, K., et al. (2025). Genetic and proteomic analysis identifies BAG3 as an amyloid-responsive regulator of neuronal proteostasis. Acta neuropathologica. https://doi.org/10.1007/s00401-025-02947-7
Vancouver
Augur ZM, Fogo GM, Arbery MR, Hsieh Y.-C, Rao NR, Goyal K, et al. Genetic and proteomic analysis identifies BAG3 as an amyloid-responsive regulator of neuronal proteostasis. Acta neuropathologica. 2025. doi:10.1007/s00401-025-02947-7. PMID: 41085772.
BibTeX
@article{augur2025-41085772,
author = {Augur, Zachary M and Fogo, Garrett M and Arbery, Mason R and Hsieh, Yi-Chen and Rao, Nalini R and Goyal, Kritika and Dexter, Emily and Bennett, David A and others},
title = {{Genetic and proteomic analysis identifies BAG3 as an amyloid-responsive regulator of neuronal proteostasis}},
journal = {Acta neuropathologica},
year = {2025},
doi = {10.1007/s00401-025-02947-7},
pmid = {41085772},
url = {https://doi.org/10.1007/s00401-025-02947-7}
}
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