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Proteostasis, Neuroinflammation and Neurodegeneration in Frontotemporal Dementia

Award Number: R01AG088324
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Proteostasis, Neuroinflammation and Neurodegeneration in Frontotemporal Dementia - Proteostasis impairment, inflammation and gliosis are linked to neurodegeneration in frontotemporal dementia (FTD) caused by GRN haploinsufficiency. FTD is the most common age-related dementia in people under 60 years of age. We showed that GRN-deficiency impairs the autophagy/lysosomal pathway (ALP) in neurons, leading to neuronal accumulation and deposition of the toxic protein TDP-43, neurodegeneration, microglial activation and inflammation. We performed proteomic studies on cortical FTD iPSC-derived neurons (iNs) and microglia (iMG), and found dysregulated levels in several proteins linked to the ALP as well as to the ubiquitin proteasome system (UPS). Some of the altered proteins have direct roles in assembly of the vATPase that is required for lysosome acidification, as well as in lysosomal trafficking; we also found dysregulated levels of several lysosomal hydrolases. We will leverage our proteomics data to look deeper into the underlying mechanisms of proteostasis dysfunction in FTD. Normally glia (microglia and astrocytes) provide support for neurons to repair damaged neurons and facilitate clearance of toxic proteins. Our new studies show that control iMG co-cultured with cortical FTD iNs display process extension toward the neurons, consistent with the healthy microglia attempting to repair patient neurons. However, when FTD i-MGs are co-cultured with control or FTD iNs, they attack and kill the neurons. The toxic actions of FTD iMGs on iNs are dramatic, but it is not clear to what extent the GRN deficiency impairs glial proteostasis, like it does in neurons, leading to hyperactivation and if the inflammatory nature of glia contributes to drive neurodegeneration in FTD or if glia are primarily responding to proteostasis impairment in GRN-deficient neurons. We hypothesize that dyshomeostasis is a unifying mechanism underlying GRN-deficient FTD. GRN deficiency impairs proteostasis in neurons, reducing clearance of toxic TDP-43 leading to neurodegeneration, and in glia causes activation of microglia and astrocytes and the ensuing inflammation further drives neurodegeneration. We will test these hypotheses by better defining the alterations in proteostasis in FTD glia by determining if autophagy flux, TDP-43 turnover and lysosomal functions are altered in a cell autonomous manner in FTD iMG, or i-astrocytes (iAs) compared to FTD iNs. We will test if FTD iMG, and iAs are hyperactivated and determine if this impairs their ALP. We will also test if neurodegeneration in FTD is driven by proteostasis impairment in glia, iNs or both and in which cell type abnormalities are evident first.


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 = $607,816 )
2026	2026	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	2	3/25/2026	NON-COMPETING CONTINUATION	$607,816
														Subtotal = $607,816

Issue Date FY: 2025 ( Subtotal = $630,496 )
2025	2025	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	1	5/16/2025	NEW	$630,496
														Subtotal = $630,496

Grand Total All Awards = $1,238,312

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Proteostasis, Neuroinflammation and Neurodegeneration in Frontotemporal Dementia

Award Number: R01AG088324

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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