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Enhanced PINK1 kinase activity as a therapeutic strategy against alpha-synuclein pathology and neurodegeneration

Award Number: RF1NS142343
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: 05/20/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Enhanced PINK1 kinase activity as a therapeutic strategy against alpha-synuclein pathology and neurodegeneration - PROJECT SUMMARY/ABSTRACT Loss-of-function mutations in the genes PINK1 and PRKN are the main cause of early-onset Parkinson’s disease (PD) and likely contribute to other, related neurodegenerative disorders too. The encoded enzymes, a ubiquitin kinase-ligase pair, cooperate to identify, label, and eliminate selectively damaged mitochondria through degradation in the autophagy-lysosome system. This quality control pathway (mitophagy) is critically important to maintain a healthy and functional mitochondrial network and is thought to broadly protect against neuronal demise and neuroinflammation. Missense mutations in, or elevated expression of, the SNCA gene lead to build-up, aggregation, and toxicity of the encoded protein alpha-synuclein (aSYN). aSYN deposits and matures into pathognomonic inclusions called Lewy bodies (LBs). Pathological aSYN is thought to seed and spread throughout the brain during progression of disease leading to widespread neurodegeneration and inflammation. Besides aSYN, LBs also seem to contain membranous remnants of mitochondrial and autophagic origin, but mechanisms leading to their formation and propagation as well as functional role(s) of these structures remain unclear. Loss of PINK1 or PRKN and elevated levels of aSYN seem to aggravate each other, but the interaction of these two major disease pathways is not well understood and the specificity is uncertain. There is considerable potential for crosstalk, convergence, or even synergism between the mitophagy and LB processes. The current project will employ a recently discovered PINK1 gain-of-function variant (PINK1G411A) that results in increased ubiquitin kinase activity, greater mitophagy rates, and enhanced resilience to stress and damage. As proof-of- concept, this new genetic model will help determine whether, how, and to which extent increasing mitophagy can also provide protection against different aspects of aSYN related disease. Toward this end, the project will interrogate the specific ability of enhanced PINK1 ubiquitin kinase activity to protect against toxicity and aggregation of aSYN, to modify seeding and spreading of the pathology, and/or to generally improve neuronal resistance to damage and inflammation. These different aspects will be evaluated in three specific aims in iPSC-derived neurons and in vivo in mouse brain using complementary models of viral aSYN overexpression or exposure to patient brain-derived pathological aSYN seeds. It is expected that the study will highlight the beneficial effects of increasing PINK1 activity and mechanistically determine how aSYN interferes with mitophagy, contributing to a better understanding of the pathobiology of LBs and future therapies.


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 = $1,875,783 )
2026	2026	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/22/2026	NEW	$1,875,783
														Subtotal = $1,875,783

Grand Total All Awards = $1,875,783

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Enhanced PINK1 kinase activity as a therapeutic strategy against alpha-synuclein pathology and neurodegeneration

Award Number: RF1NS142343

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: 05/20/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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