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Molecular mechanisms of synaptic dysfunction and cognitive decline in Huntington's disease

Award Number: R01NS110694
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: 12/15/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Molecular mechanisms of synaptic dysfunction and cognitive decline in Huntington's disease - PROJECT SUMMARY Huntington’s disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion in the HTT gene that preferentially affects medium spiny neurons (MSNs) of the striatum. HD is primarily characterized as a motor disease, but it also manifests with cognitive and behavioral deficits that appear well before motor symptoms onset and are considered the most burdensome for patients and caregivers. Cognitive changes in HD are most highly associated with functional decline and can be predictive of nursing home placement. However, the etiology of cognitive decline in HD is significantly understudied. The goal of this proposal is to provide a mechanistic understanding for how cognitive decline arises in HD. The dorsomedial striatum (DMS), the most affected area in HD, has long been recognized as an important structure in the regulation of various cognitive functions and its degeneration has been observed in patients with various forms of dementia. The striatum’s function is regulated by two major excitatory glutamatergic inputs: thalamo-striatal (T-S) and cortico- striatal (C-S). T-S synapses contribute to the regulation of cognitive flexibility, working memory, and some forms of learning, and are preferentially lost in young HD mice. Studies in HD patients before-clinical motor diagnosis found a strong thalamus–striatum association that significantly co-varies with cognitive performance and is predictive of cognitive impairment and disease progression. During the prior research period, we established a connection between the stability of T-S synapses and Heat Shock transcription Factor 1 (HSF1), a protein known for its role in protein homeostasis and stress response, in both physiology and HD. In the renewal of this R01 we are seeking to understand how HSF1 participates in the early loss of T-S synapses in HD and whether T-S synapse loss leads to cognitive decline in HD. Our preliminary HSF1 ChIP-seq analyses in young zQ175 HD mice revealed a deficit in HSF1 DNA binding onto specific postsynaptic scaffolding genes involved in synapse maintenance and HSF1 RNAi injected in the striatum of WT mice mimicked decreased T-S synapses and impaired cognition as seen in HD mice. Our previous proteomic work also revealed HSF1 interacts with unique proteins in HD that negatively influence HSF1 activity. We hypothesize that HSF1 interacts with unique proteins in HD that impair HSF1 binding and regulation of genes involved in the formation and maintenance of T-S synapses, causing T-S synapse loss and cognitive decline. We will test this hypothesis by 1) investigating the mechanism responsible for the alteration of HSF1 DNA-binding in early HD, 2) assessing how HSF1 regulates the synaptoproteome of T-S synapses, and 3) evaluating the role of HSF1- mediated loss of T-S synapses in the dysregulation of striatal synaptic plasticity and cognitive deficits in HD. Successful completion of our work will shed light into the mechanisms responsible for cognitive decline in HD and perhaps other forms of dementia in which HSF1 and DMS dysregulation have been observed.


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 = $574,149 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	4/1/2026	NON-COMPETING CONTINUATION	$574,149
														Subtotal = $574,149

Issue Date FY: 2025 ( Subtotal = $563,539 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	6/27/2025	COMPETING CONTINUATION	$564,609
2025	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/1/2025	NON-COMPETING CONTINUATION	-$1,070
														Subtotal = $563,539

Issue Date FY: 2024 ( Subtotal = $328,891 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/1/2023	NON-COMPETING CONTINUATION	$305,156
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	5/3/2024	NON-COMPETING CONTINUATION	$23,735
														Subtotal = $328,891

Issue Date FY: 2023 ( Subtotal = $339,063 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/5/2022	NON-COMPETING CONTINUATION	$305,156
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	2/1/2023	NON-COMPETING CONTINUATION	$33,907
														Subtotal = $339,063

Issue Date FY: 2022 ( Subtotal = $339,063 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/24/2022	NON-COMPETING CONTINUATION	$33,907
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/8/2021	NON-COMPETING CONTINUATION	$305,156
														Subtotal = $339,063

Issue Date FY: 2021 ( Subtotal = $337,786 )
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/30/2020	NON-COMPETING CONTINUATION	$304,007
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/18/2021	NON-COMPETING CONTINUATION	$33,779
														Subtotal = $337,786

Issue Date FY: 2020 ( Subtotal = $602,881 )
2020	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	9/18/2020	SUPPLEMENT FOR EXPANSION	$266,006
2020	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/10/2019	NEW	$336,875
														Subtotal = $602,881

Grand Total All Awards = $3,085,372

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Molecular mechanisms of synaptic dysfunction and cognitive decline in Huntington's disease

Award Number: R01NS110694

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: 12/15/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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