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Prevention of alpha-synuclein deSUMOylation as a Parkinson's therapeutic target

Award Number: R15NS121784
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: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 08/16/2024

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Prevention of alpha-synuclein deSUMOylation as a Parkinson's therapeutic target - A form of post-translational modifications (PTM), SUMOylation of target proteins has been implicated in Parkinson’s disease pathology (10), however, it is still debatable as to whether SUMOylation contributes to the disease or is a protective mechanism (9). Our recent publication using mouse models suggest that the overexpression of SUMO conjugase, Ubc9 protects dopaminergic axon tips in the striatum and cell bodies in the SN from the known PD-inducing reagent (MPTP) that results in Parkinsonian symptoms (Fig 1) (12). In addition, the MPTP treatment results in decreased SUMOylation of α-synuclein in mouse striatum (Fig 2), suggesting that MPTP-induced toxicity stimulates the deSUMO enzyme, SENP for removing SUMOs from α-synuclein, which may be associated with dopaminergic neuronal loss in the SN. Our recent results support that SENPs can be regulatory targets to prevent the deSUMOylation process that may be a part of protein aggregation and neuronal death pathway. Particularly, we identified consistently in N27 cells, mouse models and human Parkinson’s disease patients SNpc that SENP1 among known 6-7 mammalian SENPs, was significantly upregulated by MPP+ or the preformed fibrils (PFF) of α-synuclein-mediated toxicity (Figs 3,4). However, the MPTP induced toxicity does not recapitulate the typical protein aggregation-mediated PD pathology. Therefore, we adopt the recently established method using the preformed fibril (PFF) of α-synuclein for mimicking protein aggregation-mediated PD pathology. We test the hypothesis that blocking deSUMOylating enzyme, SENP1 prevents PFF-mediated toxicity in dopaminergic neurons. Using SENP1 RNAi, dominant negative, or chemical inhibitors, we will assess the target validation of SENP1 inhibition to enhance protein stability/solubility and to prevent PFF-induced protein mis-folding and aggregation. In addition, we will also verify that SENP1 expression in the SN from additional human PD midbrains was significantly higher than that in age- and gender-matched healthy controls using additional 10 samples per group. In parallel, we will assess the proteomics shifts in SUMOylation and SENPs in PFF-injected mouse brains using mass spectrometry. This study will provide new strategies for protecting dopaminergic neurons from protein aggregation-mediated toxicity that leads to Parkinson’s disease. Our potential outcome will result in meaningful publications and reveal novel target validation, as well as offering great opportunities for underrepresented (under)graduate students at an HBCU to learn essential scientific techniques and unique approaches from leading scientific groups.


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 = $0 )
2025	2022	BOISE STATE UNIVERSITY	1910 UNIVERSITY DR	BOISE	ID	83725	ADA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	11/29/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2022	DELAWARE STATE UNIVERSITY	1200 N DUPONT HWY	DOVER	DE	19901	KENT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/21/2024	NEW	-$134,619
2025	2022	BOISE STATE UNIVERSITY	1910 UNIVERSITY DR	BOISE	ID	83725	ADA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	11/22/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$134,619
2025	2022	DELAWARE STATE UNIVERSITY	1200 N DUPONT HWY	DOVER	DE	19901	KENT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	1	3/7/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $438,000 )
2022	2022	DELAWARE STATE UNIVERSITY	1200 N DUPONT HWY	DOVER	DE	19901	KENT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/30/2021	NEW	$438,000
														Subtotal = $438,000

Grand Total All Awards = $438,000

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Prevention of alpha-synuclein deSUMOylation as a Parkinson's therapeutic target

Award Number: R15NS121784

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: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 08/16/2024

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