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Activity-dependent release of human alpha-synuclein

Award Number: R21NS130256
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: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 12/08/2025

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Activity-dependent release of human alpha-synuclein - In recent years, an intriguing concept of prion-like spreading of pathogenic proteins has emerged, which has the potential to transform neurodegeneration research. Abundant neuronal protein alpha-synuclein (α-Syn) is a pathogenic protein leading to the abnormal accumulation of protein aggregates, called Lewy bodies (LBs) that cause several neurodegenerative diseases such as Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy. This prion-like spreading of α-Syn is one of the most exciting new discoveries in the progression of human neurodegenerative diseases. Nonetheless, there are critical gaps in our understanding of α-Syn spreading regarding genetic & molecular factors regulating α-Syn spreading, its molecular identity and release/uptake mechanisms. New insights into the molecular mechanisms of α-Syn propagation will uncover potential therapeutic targets for slowing or even halting PD progression. What is needed is a new genetic model to speed improved mechanistic understanding. In this proposal, we are especially interested in activity-dependent release of α-Syn since known PD risk factors such as traumatic brain injury (TBI) and sleep deprivation increases neuronal activity and extracellular levels of α-Syn. The goal of this proposed study is to explore how α-Syn spreads between cells in the nervous system. Specifically, we are interested in studying how α-Syn mutations and genetic/molecular factors affect its activity-dependent release. Aim 1 is to characterize molecular and biochemical profiles of released α-Syn by neuronal activity. In Aim 2, we will examine whether five α-Syn mutations (A30P, E46K, H50Q, G51D & A53T) differently affect activity-dependent release. In Aim 3, we will examine whether activity-dependent α-Syn release is affected by other PD genes and environmental factors. Three groups of PD causing factors will be examined in this aim: Group 1. PD genes (e.g., LRRK2) causing defects in protein degradation and loss of proteostasis. Group 2. PD genes (e.g., parkin) involved in mitochondrial dysfunction and oxidative stress in PD. Group3. Environmental PD factors (e.g., rotenone).


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 = $0 )
2026	2023	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/13/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = -$51,054 )
2025	2023	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	4/25/2025	NEW	$0
2025	2023	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/16/2025	NEW	-$51,054
														Subtotal = -$51,054

Issue Date FY: 2023 ( Subtotal = $403,010 )
2023	2023	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/1/2023	NEW	$403,010
2023	2023	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	3/6/2023	NEW	$0
														Subtotal = $403,010

Grand Total All Awards = $351,956

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Activity-dependent release of human alpha-synuclein

Award Number: R21NS130256

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: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 12/08/2025

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