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Unraveling BAG6 Function in UBQLN2-Associated ALS/FTD: Insights into Proteostasis and Neurodegeneration

Award Number: R21AG098513
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Unraveling BAG6 Function in UBQLN2-Associated ALS/FTD: Insights into Proteostasis and Neurodegeneration - Project summary Proteostasis dysfunction and pathological protein aggregation are strongly linked to the development of amyotrophic lateral sclerosis, frontotemporal dementia (ALS/FTD) and other neurodegenerative diseases (NDs); however, therapeutic avenues targeting proteotoxicity in these diseases remain limited. In this exploratory R21 application I will investigate the role of the molecular chaperone BAG6 as a potential suppressor of neurodegeneration in cellular and mouse models of Ubiquilin-2 (UBQLN2)–associated ALS/FTD. UBQLN2 is a ubiquitin chaperone that directs ubiquitylated clients to the proteasome or autophagosome for degradation. ALS- linked mutations within its proline-rich repeat (PRR) domain disrupt this function, but current rodent models incompletely capture disease-relevant UBQLN2 misfolding and toxicity, limiting mechanistic discovery. To overcome these barriers, we generated a humanized UBQLN24XALS knock-in mouse model carrying a combination of clinically observed ALS mutations, which exhibits robust UBQLN2 aggregation and neurotoxicity. Complementary studies in Drosophila and iPSC-derived motor neurons (iMNs) reveal heightened UBQLN2 misfolding. In iMNs, UBQLN24XALS formed prominent aggregates throughout cell bodies and axons, accompanied by reductions in total, primary, and branch neurite lengths. Proteomic analyses of wild-type and UBQLN24XALS iMNs identified BAG6—a central component of the guided entry of tail-anchored (GET) protein pathway—as an enriched UBQLN24XALS interactor. BAG6 depletion decreased UBQLN2 solubility and increased levels of the shared client protein PEG10, supporting a key role for BAG6 in maintaining proteostasis. UBQLN2 interacts with BAG6 in mouse brain lysates and colocalizes with BAG6 in hippocampal neurons. Building on these findings, this proposal will: (1) Define how BAG6–UBQLN2 interactions regulate proteostasis by testing whether BAG6 prevents UBQLN2 misfolding or whether UBQLN2 mutations impair BAG6-dependent substrate triage. (2) Determine whether BAG6 modifies UBQLN2-mediated neurodegeneration in UBQLN24XALS mice by assessing: (i) whether AAV-mediated BAG6 knockdown accelerates UBQLN2 aggregation and neurological decline in UBQLN24XALS mice, and (ii) testing whether BAG6 overexpression mitigates inclusion pathology and disease progression in UBQLN24XALS mice. Together, these studies will provide critical mechanistic insight into ALS/FTD- UBQLN2 and uncover BAG6-dependent proteostasis pathways with broad relevance to other neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $427,625 )
2026	2026	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Aging Research	000	1	8/20/2026	NEW	$427,625
														Subtotal = $427,625

Grand Total All Awards = $427,625

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Unraveling BAG6 Function in UBQLN2-Associated ALS/FTD: Insights into Proteostasis and Neurodegeneration

Award Number: R21AG098513

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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