Sunday, October 12, 2025 10/12/2025

Rhes-SUMO Pathway in Huntington Disease

Award Number: R01NS128225
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: 09/21/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Rhes-SUMO Pathway in Huntington Disease - The polyglutamine expansion in the huntingtin (mHTT) causes HD. Before HD onset, striatal atrophy occurs, with subsequent loss of cortico-striatal white matter (WM) connections in layer V. As HD progresses, it affects other parts of the brain and the peripheral tissues. The mechanisms underlying the neuronal vulnerability in HD are not entirely understood and likely several, including aggregation, transcriptional dysregulation, energy metabolism deficits, synaptic dystrophy, oxidative stress, inflammation, and others. We demonstrated that striatal enriched protein Rhes interacts with mHTT via the farnesylation domain and promotes cellular toxicity by increasing the soluble forms of mHTT via small ubiquitin-like modifier (SUMO)-1 modification. However, the mechanisms by which the Rhes-SUMO pathway mediates neuronal vulnerability in HD are unclear. We hypothesize that Rhes and SUMO1 signaling circuitry orchestrate striatal vulnerability and HD progression by altering mHTT levels and promoting the spread of mHTT in the brain. This hypothesis is formulated based on the following findings: a) Rhes mediates mHTT transmission between cultured neurons involving actin-based tunneling nanotube-like (TNT-like) membranous protrusions, b) SUMO depletion or SUMO-defective mHTT diminishes transport of mHTT via Rhes–TNTs. c) SUMO1 deletion enhances autophagy activities and decreases mHTT abundance in the striatum and prevents HD-related behavioral and anatomical deficits in Q175HD KI mice, and d) Rhes transits within striatum and from the striatum to the cortex (V, VI, layers) and spread mHTT. These data indicate an intricate link between Rhes and SUMO pathways in HD pathogenesis. But the detailed mechanism of action(s) of Rhes–SUMO1 pathways in HD is unclear. This proposal addresses two distinct yet interrelated Aims: Aim 1. To uncover the role and mechanisms of Rhes-mediated mHTT spreading in the brain. Here will test the hypothesis that Rhes spreads mHTT and promotes neuropathology involving posttranslational mechanisms and TNT-like routes. Aim 2. To identify the mechanisms of SUMO1- mediated HD pathogenesis. Here we test the hypothesis that SUMO1–mHTT inhibits autophagy, thereby allowing accumulation and spread of mHTT from the striatum to the cortex. This project will provide novel mechanistic insights into SUMO-mediated autophagy deficits in HD and SUMO roles in Rhes-mediated mHTT transport between brain regions while also potentially identifying novel therapeutic targets that can limit mHTT spread in the HD brain.


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 = -$22,659 )
2025	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	9/25/2025	SUPPLEMENT FOR EXPANSION	-$14,428
2025	2024	FLORIDA ATLANTIC UNIVERSITY	777 GLADES RD	BOCA RATON	FL	33431	PALM BEACH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	9/25/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$119,008
2025	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	9/25/2025	NON-COMPETING CONTINUATION	-$127,239
														Subtotal = -$22,659

Issue Date FY: 2024 ( Subtotal = $434,028 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	8/27/2024	SUPPLEMENT FOR EXPANSION	$27,550
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	7/29/2024	SUPPLEMENT FOR EXPANSION	$7,141
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	8/26/2024	NON-COMPETING CONTINUATION	$399,337
2024	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/19/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $434,028

Issue Date FY: 2023 ( Subtotal = $552,173 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	9/6/2023	SUPPLEMENT FOR EXPANSION	$69,173
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/24/2023	NON-COMPETING CONTINUATION	$483,000
														Subtotal = $552,173

Issue Date FY: 2022 ( Subtotal = $483,000 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/21/2022	NEW	$483,000
														Subtotal = $483,000

Grand Total All Awards = $1,446,542

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Rhes-SUMO Pathway in Huntington Disease

Award Number: R01NS128225

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: 09/21/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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