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Molecular and cellular mechanisms of spinocerebellar ataxia type 5

Award Number: R15NS116511
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: 03/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Molecular and cellular mechanisms of spinocerebellar ataxia type 5 - β-III-spectrin is a key cytoskeletal protein that localizes to the soma and dendrites of cerebellar Purkinje neurons, and is required for dendritic arborization and signaling. Dominant mutations in the SPTBN2 gene encoding β-III-spectrin cause the neurodegenerative disorder spinocerebellar ataxia type 5 (SCA5). SCA5 causes degeneration of Purkinje cells, and an associated progressive gait and limb ataxia. There is no cure or therapy for SCA5. Many SCA5 missense mutations (including L253P) cluster within the β-III-spectrin actin- binding domain (ABD). Previously, we showed that increased actin binding is a shared molecular consequence of the ABD-localized mutations. Using novel Drosophila models, we demonstrated that a common cellular consequence of the ABD-localized mutations is reduced dendritic arborization. We further determined that truncation of the unique β-III-spectrin N-terminal domain (NTD), preceding the conserved ABD, rescues L253P-induced high-affinity actin binding and arbor defects. We also discovered that multiple phosphosites modulate the binding of wild-type β-III-spectrin to actin in vitro. However, it remains unclear how increased actin binding impairs the function of β-spectrin to support dendritic arborization. Moreover, the shared impact of SCA5 mutations to alter actin binding demands a better understanding of the mechanisms controlling β-spectrin-actin interactions. The objective of this application is to determine how SCA5-induced high-affinity actin binding leads to decreased dendritic arborization, and to elucidate mechanisms regulating spectrin-actin binding. In addition to the progress described above, using immunoprecipitation coupled to mass spectrometry, we identified numerous proteins in Drosophila neurons that physically associate with β- spectrin, including tropomyosin, myosins, kinases, phosphatases, and additional proteins. Intriguingly, tropomyosin, was recently shown to simultaneously bind actin and the unique β-spectrin NTD, suggesting tropomyosin is a key regulator of spectrin-actin binding. Further, tropomyosin loss-of-function alleles are known to increase dendritic arbor outgrowth. This suggests that modulation of tropomyosin, or other components of the interactome, may alleviate reduced arborization caused by SCA5 mutations. In this project we will define the Drosophila neuronal interactomes of the wild-type and L253P β-spectrin. We will use these interactomes and the well-developed Drosophila toolbox to guide a targeted genetic modifier screen for modulators of SCA5 arbor defects. Further, we will define in greater detail how the NTD, and its phosphorylation and binding to tropomyosin, regulates actin binding and SCA5 arbor defects. Numerous undergraduate students will participate in the execution of this project, providing important bench training for the next generation of problem solvers.


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 = $505,394 )
2025	2025	OAKLAND UNIVERSITY	2200 N SQUIRREL RD	ROCHESTER	MI	48309	OAKLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/8/2025	COMPETING CONTINUATION	$505,394
														Subtotal = $505,394

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2020	OAKLAND UNIVERSITY	2200 N SQUIRREL RD	ROCHESTER	MI	48309	OAKLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/15/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	OAKLAND UNIVERSITY	2200 N SQUIRREL RD	ROCHESTER	MI	48309	OAKLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/31/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $398,006 )
2020	2020	OAKLAND UNIVERSITY	2200 N SQUIRREL RD	ROCHESTER	MI	48309	OAKLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/18/2020	NEW	$398,006
														Subtotal = $398,006

Grand Total All Awards = $903,400

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Molecular and cellular mechanisms of spinocerebellar ataxia type 5

Award Number: R15NS116511

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: 03/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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