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Pum2-dependent translational regulation of a-SYN near mitochondria and contribution to the pathogenesis of Parkinson's disease

Award Number: R01NS101461
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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Alpha-synuclein (α-SYN) and mitochondrial dysfunction are two central components in Parkinson's disease (PD) pathogenesis. Mitochondrial dysfunction is a common feature of the many iterations of PD pathogenesis and α-SYN toxicity seems to affect mitochondria most significantly. Complex interplay between α-SYN and mitochondria has been widely observed. While the intricate crosstalk between mitochondria and α-SYN is poorly understood, our preliminary studies suggest that the 3'-untranslated region (3'-UTR) of α-SYN mRNA plays a key role in translational regulation of α-SYN near mitochondria. Our preliminary findings demonstrate that 1) α-SYN mRNA is localized to the mitochondrial surface where its translation is initiated by mitochondrial ROS; 2) this translational control is governed by Pum2, a RNA-binding translational repressor, which binds to the 3'-untranslated region (3'-UTR) of α-SYN transcript; 3) interestingly, mitochondrial Pum2 levels in post-mortem PD brain were significantly lower compared to control subjects, while α-SYN levels were opposite, implying Pum2’s repressive role on α-SYN near mitochondria. In addition, recent studies showing the association of single nucleotide polymorphisms in the α-SYN 3'-UTR with PD strongly suggest that 3`-UTR-mediated regulation of α-SYN could become a critical player in PD pathogenesis. Our central hypothesis is that deregulation of Pum2-mediated α-SYN translational repression on the outer surface of mitochondria contributes to mitochondrial dysfunction observed in PD. The following three specific aims will be pursued: In Aim 1, both the cis-regulatory elements and the trans- factors responsible for mitochondrial localization of α-SYN will be identified. In Aim 2, it will be determined how mitochondrial ROS controls Pum2-mediated translation of α-SYN mRNA and the roles of newly synthesized α- SYN. In Aim 3, it will be investigated whether PD-associated SNPs in the 3'-UTR of α-SYN cause changes in Pum2 binding, translocation of the protein to mitochondria, and mitochondrial functions. The successful completion of this project could create a paradigm shift in our understanding of molecular mechanisms that control α-SYN expression near mitochondria in PD pathogenesis by elucidating the role of Pum2 and the 3'-UTR of α-SYN in translational regulation


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	RUTGERS, THE STATE UNIVERSITY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	10/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $343,438 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/31/2022	NON-COMPETING CONTINUATION	$343,438
														Subtotal = $343,438

Issue Date FY: 2021 ( Subtotal = $343,438 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/20/2021	NON-COMPETING CONTINUATION	$343,438
2021	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	5/23/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$129,186
2021	2019	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/23/2021	NON-COMPETING CONTINUATION	-$129,186
														Subtotal = $343,438

Issue Date FY: 2020 ( Subtotal = $341,250 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	8/24/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$341,250
2020	2019	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/21/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $341,250

Issue Date FY: 2019 ( Subtotal = $325,938 )
2019	2019	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CNTRL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/3/2019	NON-COMPETING CONTINUATION	$325,938
2019	2018	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CNTRL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/1/2019	NEW	$0
														Subtotal = $325,938

Issue Date FY: 2018 ( Subtotal = $325,938 )
2018	2018	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CNTRL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/10/2018	NEW	$325,938
														Subtotal = $325,938

Grand Total All Awards = $1,680,002

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Pum2-dependent translational regulation of a-SYN near mitochondria and contribution to the pathogenesis of Parkinson's disease

Award Number: R01NS101461

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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