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Mechanisms of Synaptic Dysfunction in Parkinson s and Other Synuclein-Linked Diseases

Award Number: R01NS078165
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: 01/15/2012
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Mechanisms of Synaptic Dysfunction in Parkinson s and Other Synuclein-Linked Diseases - PROJECT ABSTRACT Aggregation of α-synuclein throughout the neuron, including at synapses, is a pathological hallmark of Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and variants of Alzheimer’s disease (AD). Synaptic aggregation of α-synuclein is strongly associated with cognitive deficits and dementia in PD and DLB. The long-term goal of this project is to identify the cellular and molecular mechanisms that give rise to α-synuclein-induced synaptic deficits and to develop strategies for reversing them. While it is generally agreed that α-synuclein accumulation at synapses impairs synaptic vesicle trafficking, the underlying mechanisms remain unclear, preventing the development of treatments for improving synaptic function in PD and DLB. Over the last decade, we developed and implemented lamprey reticulospinal synapses as a new model for studying how α-synuclein accumulation impacts synapse structure and function. Our lab was the first to discover that acutely introducing excess α-synuclein to synapses, mimicking increased expression in PD and DLB, inhibits synaptic vesicle endocytosis. This result was subsequently corroborated at mammalian synapses. We then discovered that different molecular species of α-synuclein (e.g. monomers vs. dimers) cause distinct impacts on endocytosis, emphasizing the need to understand how each species affects synaptic vesicle trafficking and the underlying mechanisms. Experiments proposed here will significantly advance the field by: determining how post-translational modifications of α-synuclein alter its effects at synapses (Aim 1); identifying how α-synuclein oligomers purified from human PD and DLB brains affect synapses (Aim 2); and examining the underlying mechanisms with selective inhibitors of α-synuclein membrane binding and oligomerization (Aim 3). The project is significant because it will substantially increase our understanding of the impacts of excess α-synuclein on synapses, including pathology-associated strains, and it will provide initial testing of α-synuclein inhibitors with therapeutic potential while also probing the molecular mechanisms.


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: 2025 ( Subtotal = $616,013 )
2025	2025	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	6/26/2025	EXTENSION WITH OR WITHOUT FUNDS	$616,013
														Subtotal = $616,013

Issue Date FY: 2023 ( Subtotal = -$175,500 )
2023	2021	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	7/13/2023	NON-COMPETING CONTINUATION	-$175,500
														Subtotal = -$175,500

Issue Date FY: 2021 ( Subtotal = $501,073 )
2021	2021	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	5/5/2021	NON-COMPETING CONTINUATION	$501,073
														Subtotal = $501,073

Issue Date FY: 2020 ( Subtotal = $564,113 )
2020	2020	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	5/18/2020	NON-COMPETING CONTINUATION	$564,113
														Subtotal = $564,113

Issue Date FY: 2019 ( Subtotal = $661,495 )
2019	2019	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	6/11/2019	NON-COMPETING CONTINUATION	$612,804
2019	2019	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	1/15/2019	SUPPLEMENT FOR EXPANSION	$48,691
														Subtotal = $661,495

Issue Date FY: 2018 ( Subtotal = $505,993 )
2018	2018	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	8	5/31/2018	NON-COMPETING CONTINUATION	$505,993
2018	2017	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	2/15/2018	COMPETING CONTINUATION	$65
2018	2016	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	2/15/2018	EXTENSION WITH OR WITHOUT FUNDS	-$65
														Subtotal = $505,993

Issue Date FY: 2017 ( Subtotal = $498,248 )
2017	2017	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	7	8/3/2017	COMPETING CONTINUATION	$413,855
2017	2017	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	006	7	8/30/2017	COMPETING CONTINUATION	$84,393
2017	2016	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	6	1/26/2017	EXTENSION WITH OR WITHOUT FUNDS	-$1
2017	2016	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	1/22/2017	EXTENSION WITH OR WITHOUT FUNDS	$65,488
2017	2016	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	6	8/30/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
2017	2015	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	1/26/2017	NON-COMPETING CONTINUATION	$1
2017	2015	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/22/2017	NON-COMPETING CONTINUATION	-$65,488
														Subtotal = $498,248

Issue Date FY: 2016 ( Subtotal = $284,385 )
2016	2016	MARINE BIOLOGICAL LABORATORY	7 MBL STREET	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	1/7/2016	EXTENSION WITH OR WITHOUT FUNDS	$284,385
														Subtotal = $284,385

Issue Date FY: 2015 ( Subtotal = $315,984 )
2015	2015	MARINE BIOLOGICAL LABORATORY	7 MBL STREET	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	1/6/2015	NON-COMPETING CONTINUATION	$31,599
2015	2015	MARINE BIOLOGICAL LABORATORY	7 MBL STREET	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/22/2014	NON-COMPETING CONTINUATION	$284,385
														Subtotal = $315,984

Issue Date FY: 2014 ( Subtotal = $312,824 )
2014	2014	MARINE BIOLOGICAL LABORATORY	7 MBL STREET	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/20/2014	NON-COMPETING CONTINUATION	$284,387
2014	2014	MARINE BIOLOGICAL LABORATORY	7 MBL STREET	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	3/7/2014	NON-COMPETING CONTINUATION	$28,437
														Subtotal = $312,824

Issue Date FY: 2013 ( Subtotal = $304,924 )
2013	2013	MARINE BIOLOGICAL LABORATORY	7 MBL STREET	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	1/4/2013	NON-COMPETING CONTINUATION	$284,387
2013	2013	MARINE BIOLOGICAL LABORATORY	7 MBL STREET	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	5/21/2013	NON-COMPETING CONTINUATION	$20,537
2013	2012	MARINE BIOLOGICAL LABORATORY	7 MBL STREET	WOODS HOLE	MA	02543	BARNSTABLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/16/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$243,251
2013	2012	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	11/16/2012	NEW	-$243,251
														Subtotal = $304,924

Issue Date FY: 2012 ( Subtotal = $315,613 )
2012	2012	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/14/2012	NEW	$315,613
														Subtotal = $315,613

Grand Total All Awards = $4,705,165

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Mechanisms of Synaptic Dysfunction in Parkinson s and Other Synuclein-Linked Diseases

Award Number: R01NS078165

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: 01/15/2012

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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