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Endolysosomal defects in secretory autophagy and microglial toxicity in FTD

Award Number: R01AG057462
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2017
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Endolysosomal defects in secretory autophagy and microglial toxicity in FTD - PROJECT SUMMARY Glial pathology is increasingly recognized as a key feature in neurodegenerative diseases. However, the exact mechanisms that promotes glial pathology remain unclear. Several studies implicate the autophagy machinery, a highly conserved lysosomal degradation pathway, in maintaining protein homeostasis in neurons during brain aging and neurodegeneration. In addition, autophagy regulates the check-and-balance of microglia-mediated inflammatory response to misfolded proteins, including β-amyloid peptides, hyperphosphorylated Tau, and TDP- 43, which accumulate during neurodegeneration. Collectively, these results underscore the critical and cell type- specific role of the autophagy machinery in maintaining neuron-glia homeostasis by regulating the trafficking of intracellular organelles and cargoes, such as misfolded proteins. In the previous funding period, we uncovered new autophagy-dependent secretory processes in non-neuronal and glial cells, including most notably, LC3- dependent extracellular vesicle loading and secretion (LDELS). LDELS targets include RNA binding proteins and extracellular vesicle (EV) cargoes that have been implicated in the pathogenesis of frontotemporal dementia (FTD). In addition, our results showed that loss of function in FTD gene Progranulin (Grn) leads to age-dependent endolysosomal defects and hypersecretory phenotypes in microglia that promotes neuronal loss and abnormal accumulation of the RNA binding protein TDP-43 in Grn-/- mouse brain. Together, these results underscore the important roles of autophagy and endolysosomal trafficking in microglial activation in FTD. In follow up studies, we have further expanded the scope of our work and identified a highly regulated mechanism, Secretory Autophagy during Lysosome Inhibition (SALI), which is critically dependent on multiple ATGs for autophagosome formation and on Rab27a for vesicle exocytosis. Using TMT-based quantitative proteomics, we uncovered that loss of Progranulin leads to a marked increase in unconventional myosin Myo5a, a known Rab27a interacting partner. Given the well-documented role of Rab27a and Myo5a in the transport of intracellular organelles, these results broach the hypothesis that blockage of endolysosomal trafficking disrupts microglial homeostasis and promotes secretory autophagy and neurodegeneration in Grn-/- mice. To test this hypothesis, we will: 1) Delineate how FTD-associated endolysosomal defects influence secretory autophagy and dissect the effects of SALI on intracellular homeostasis; 2) Scrutinize how secretory autophagy and endolysosomal defects in microglia impact lipid metabolism and microglial toxicity; and 3) Determine whether genetic autophagy loss mitigates microglial toxicity and neurodegeneration in Progranulin-deficient mice. Together, the studies proposed in this renewal harness the unique expertise in Drs. Huang and Debnath’s laboratories and provide critical insights on how SALI controls the delicate balance of secretion and intracellular trafficking of disease-relevant proteins in microglia to promote neurodegeneration in FTD.


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 = $713,896 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Aging Research	000	10	3/24/2026	NON-COMPETING CONTINUATION	$713,896
														Subtotal = $713,896

Issue Date FY: 2025 ( Subtotal = $699,618 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Aging Research	001	9	6/18/2025	NON-COMPETING CONTINUATION	$57,112
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Aging Research	000	9	3/14/2025	NON-COMPETING CONTINUATION	$642,506
														Subtotal = $699,618

Issue Date FY: 2024 ( Subtotal = $713,896 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Aging Research	000	8	4/18/2024	NON-COMPETING CONTINUATION	$713,896
														Subtotal = $713,896

Issue Date FY: 2023 ( Subtotal = $713,943 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	000	7	3/28/2023	NON-COMPETING CONTINUATION	$713,896
2023	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	001	5	5/11/2023	NON-COMPETING CONTINUATION	$47
														Subtotal = $713,943

Issue Date FY: 2022 ( Subtotal = $713,896 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	001	6	5/17/2022	COMPETING CONTINUATION	$713,896
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	003	6	9/28/2022	COMPETING CONTINUATION	$40,006
2022	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	002	5	9/28/2022	NON-COMPETING CONTINUATION	-$40,006
2022	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	000	5	5/6/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $713,896

Issue Date FY: 2021 ( Subtotal = $650,216 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	000	5	5/19/2021	NON-COMPETING CONTINUATION	$650,216
														Subtotal = $650,216

Issue Date FY: 2020 ( Subtotal = $650,216 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	000	4	6/1/2020	NON-COMPETING CONTINUATION	$650,216
														Subtotal = $650,216

Issue Date FY: 2019 ( Subtotal = $666,066 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	000	3	4/22/2019	NON-COMPETING CONTINUATION	$666,066
														Subtotal = $666,066

Issue Date FY: 2018 ( Subtotal = $666,066 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Aging Research	000	2	6/8/2018	NON-COMPETING CONTINUATION	$666,066
														Subtotal = $666,066

Issue Date FY: 2017 ( Subtotal = $666,066 )
2017	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Aging Research	000	1	9/15/2017	NEW	$666,066
														Subtotal = $666,066

Grand Total All Awards = $6,853,879

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Endolysosomal defects in secretory autophagy and microglial toxicity in FTD

Award Number: R01AG057462

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2017

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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