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Genetic Analysis of Neurodegeneration

Award Number: R35NS132225
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: 05/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Genetic Analysis of Neurodegeneration - Neurodegenerative diseases are common and devastating disorders, which will become increasingly prevalent as our population ages. Unfortunately, despite years of effort and some promising leads, we still do not have disease-modifying therapies. To provide an alternative approach to studying these disorders and identifying potential therapeutics we have pioneered the use of Drosophila as a model system for studying neurodegeneration, with a particular emphasis on Parkinson’s disease and Alzheimer’s disease. Our studies have allowed us to identify genes controlling neurodegeneration in our fly models. We have subsequently verified these findings in vertebrate models of the diseases, in postmortem brain tissue from patients and in patient-derived cells. In the current proposal we will capitalize on our prior progress by exploring in mechanistic detail the role alterations of the spectrin cytoskeleton play in promoting neurodegeneration in α-synucleinopathies. Specifically, we will test the hypothesis that α-synuclein binds to the ankyrin-binding domain of ß-spectrin and thereby perturbs autophagosome transport and maturation. We have recently developed a powerful new model of α-synuclein toxicity in Drosophila. Our previous model showed striking specificity for dopaminergic neurons. While valuable for exploring toxicity to dopamine neurons, a very important cell type for Parkinson’s disease, the restricted pathology present limited implementation of large-scale genetic screens. We have therefore created a model of α-synuclein neurotoxicity in which age-dependent neurodegeneration is significantly more widespread. Our new model has facilitated completion of a genome-scale genetic screen, an important strength of Drosophila models. Importantly, our new α-synucleinopathy model employs a dual transcriptional system we have developed, which allows simultaneous and independent manipulation of gene expression, at scale, in neurons and glia. We can now define the broad complement of mechanisms by which glia control toxicity of α-synuclein in neurons non-cell autonomously. Given the growing evidence for an important role for glia in neurodegenerative disease, these studies have the potential for significant impact.


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 = $921,694 )
2026	2026	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/28/2026	NON-COMPETING CONTINUATION	$921,694
2026	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/25/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $921,694

Issue Date FY: 2025 ( Subtotal = $921,694 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/22/2025	NON-COMPETING CONTINUATION	$921,694
														Subtotal = $921,694

Issue Date FY: 2024 ( Subtotal = $894,043 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/29/2024	NON-COMPETING CONTINUATION	$894,043
														Subtotal = $894,043

Issue Date FY: 2023 ( Subtotal = $921,694 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/1/2023	NEW	$921,694
														Subtotal = $921,694

Grand Total All Awards = $3,659,125

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Genetic Analysis of Neurodegeneration

Award Number: R35NS132225

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: 05/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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