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Structural and Molecular Mechanisms for Dysregulation of Protein Kinase C Gamma in Cerebellar Ataxia

Award Number: R01NS120725
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Structural and Molecular Mechanisms for Dysregulation of Protein Kinase C Gamma in Cerebellar Ataxia - Summary/Abstract The overall vision of our proposed research is to understand the structural, molecular, and cellular mechanisms by which germline mutations in protein kinase C gamma (PKCg) drive the neuro- degenerative disease Spinocerebellar Ataxia 14 (SCA14). PKCg is a Ca2+/diacylglycerol-regulated kinase expressed only in neurons, including Purkinje cells whose degeneration is a hallmark of the almost 50 subtypes of SCA. We have assembled a team with extensive and complementary expertise in structural biology of kinases and in PKC mechanisms to understand how these mutations alter the structure and function of PKCg to contribute to the disease phenotype. The hypothesis driving this proposal is that mutations are concentrated at specific regions of PKCg that break autoinhibitory contacts to enhance its activity by a novel mechanism that evades normal quality control degradation. This evasion of degradation may be a unique feature of the Ataxia mutations as cancer-associated mutations that break autoinhibitory contacts destabilize PKC and shunt it to degradation. Such evasion of normal quality control allows aberrantly active PKCg to enhance its signaling output, which in Purkinje cells in the cerebellum leads to degeneration. Furthermore, we hypothesize that enhanced signaling by PKCg may underlie the pathology of SCA, in general, as a large fraction of SCAs are caused by mutations in proteins that control Ca2+ homeostasis or signaling. We aim to combine computational, structural, biochemical, live-cell imaging, and phosphoproteomics approaches to understand the molecular details of how disease-associated mutations in PKCg impact function, with the long-term future goal of using this knowledge to treat this devastating disease.


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 = $587,716 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/25/2025	NON-COMPETING CONTINUATION	$587,716
														Subtotal = $587,716

Issue Date FY: 2024 ( Subtotal = $633,428 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/11/2024	NON-COMPETING CONTINUATION	$45,712
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/12/2024	NON-COMPETING CONTINUATION	$587,716
														Subtotal = $633,428

Issue Date FY: 2023 ( Subtotal = $653,017 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/30/2023	NON-COMPETING CONTINUATION	$653,017
														Subtotal = $653,017

Issue Date FY: 2022 ( Subtotal = $653,017 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/7/2022	NON-COMPETING CONTINUATION	$653,017
														Subtotal = $653,017

Issue Date FY: 2021 ( Subtotal = $667,016 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/19/2021	NEW	$667,016
														Subtotal = $667,016

Grand Total All Awards = $3,194,194

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Structural and Molecular Mechanisms for Dysregulation of Protein Kinase C Gamma in Cerebellar Ataxia

Award Number: R01NS120725

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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