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Enhancing Mask/ANKHD1 activity to protect against Tau-induced neurodegeneration

Award Number: R21NS123861
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Enhancing Mask/ANKHD1 activity to protect against Tau-induced neurodegeneration - Enhancing Mask/ANKHD1 activity to protect against Tau-induced neurodegeneration Abstract A common pathophysiological feature of both inherited and sporadic neurodegenerative diseases such as Alzheimer’s disease is the cytoplasmic accumulation of inclusions containing aggregate-prone proteins such as Tau. Mounting evidence also suggested that such abnormal inclusions in neurons and glial cells of neurodegenerative disease patients can spread across cellular boundaries within the nervous system in a prion-like manner. Therefore, enhancing the clearance of the toxic protein aggregates holds tremendous therapeutic potential for treating neurodegeneration. We found that upregulating Mask – a conserved Ankyrin repeats and KH domain protein (the human homologue is called ANKHD1) – in fly neurological disease model markedly suppresses human mutant Tau-, FUS- and TDP-43-induced degeneration. We next obtained biochemical, cellular, and genetic evidence that Mask is both necessary and sufficient to promote clearance of ubiquitinated proteins, and it does so by promoting lysosomal acidification and enhancing the flux of autophagy. We also found that the mammalian homologue of Mask, ANKHD1, may also promote autophagic flux. These results led us to hypothesize that enhancing Mask/ANKHD1 activity promotes the autophagy/lysosomal pathway, which has an overall beneficial effect in removing of toxic protein aggregates, and therefore may have the potential to be further developed and tested as a therapeutic strategy for Alzheimer’s disease. This grant aims to test 1) whether Mask-mediated promotion of lysosomal function suppresses neurodegeneration induced by human Tau in flies; and 2) whether ANKHD1 co-expression suppresses neuron-specific degeneration induced by human mutated Tau in mouse models.


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 = -$1,034 )
2026	2021	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/20/2025	NEW	-$1,034
														Subtotal = -$1,034

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/17/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER-NEW ORLEANS	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/26/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $404,250 )
2021	2021	LOUISIANA STATE UNIVERSITY SYSTEM	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/13/2021	NEW	$404,250
														Subtotal = $404,250

Grand Total All Awards = $403,216

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Enhancing Mask/ANKHD1 activity to protect against Tau-induced neurodegeneration

Award Number: R21NS123861

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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