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Alpha-synuclein aggregation disrupts motility, synaptic transmission, and calcium signaling in the myenteric plexus of the rat colon

Award Number: R01DK108798
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Parkinson's disease (PD) is typically recognized as a somatic motor disorder. However, gastrointestinal motor dysfunction resulting in constipation is often described as having a greater negative impact on the quality of life than somatic motor dysfunction. Moreover, GI dysfunction complicates the clinical management of PD as it interferes with the absorption of levodopa, the standard treatment for PD motor symptoms. The protein alpha- synuclein (a-syn) is linked to CNS degeneration and is present in aggregated forms in neurons throughout the enteric nervous system (ENS). Overexpression of a-syn in specific populations of DA neurons in the CNS results in a-syn aggregation, altered neurotransmission, and neurodegeneration; providing a model with high face validity for PD. However, to date, no attempts have been made linking pathological enteric a-syn to GI dysfunction. To that end, we developed a novel gene delivery method whereby we can direct transgene expression specifically to enteric neurons. Importantly, this approach limits all transgene expression to the ENS with no expression seen in central neurons, muscle, or other organs. In other words, we have developed a novel platform by which to study ENS function without adding confound of using systemically applied agents such as toxicants or the use of transgenic animals with ubiquitous transgene expression. Using this approach we delivered adeno-associated virus (AAV) expressing a-syn to the descending colon. Within one month of vector delivery the animals displayed a significant decrease in fecal output, decreased inhibitory neuromuscular transmission, and decreased basal levels of calcium in neurons and enteric glia, without neuronal loss in the treated ENS. a-syn has a role in synaptic vesicle exocytosis, recycling, and docking, and aggregation of a-syn results in impaired neurotransmission. We therefore hypothesize that a-syn contributes to GI dysfunction, and that this effect is mediated via impaired synaptic transmission, resulting in a net increase of the inhibitory tone of the ENS. Herein we propose to (1) Determine whether a-syn aggregation is required for the observed colonic dysmotility. (2) Determine whether overexpression of a-syn results in a net increase in the inhibitory tone of ENS neurotransmission and whether this impairs propulsive motility. (3). Determine whether a-syn overexpression impairs enteric ganglionic neurotransmission. We will perform these analyses by using vectors that encode different isoforms of a-syn (wildtype, hyper-aggregatable, and non-aggregatable). We will compare the data observed in treated rats and mice with transgenic a-syn overexpressing animals. We will also determine whether a-syn overexpression in inhibitory motor neurons (the population of ENS neurons most often associated with a-syn pathology in PD) per se is sufficient to elicit GI dysfunction. Together the aims in this proposal intend to demonstrate that aggregated a-syn in the ENS causes GI dysfunction, and to define the molecular etiology underlying GI dysfunction in PD. This work will thus provide a basis for future research efforts focused on investigating new treatments of this devastating comorbidity in PD.


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: 2023 ( Subtotal = $0 )
2023	2021	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/1/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $367,016 )
2021	2021	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/5/2021	NON-COMPETING CONTINUATION	$367,016
2021	2021	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	9/15/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $367,016

Issue Date FY: 2020 ( Subtotal = $367,016 )
2020	2020	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	3/5/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$367,016
2020	2020	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	4	4/3/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$637,345
2020	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	4/3/2020	NON-COMPETING CONTINUATION	-$348,750
2020	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/28/2020	NON-COMPETING CONTINUATION	$0
2020	2018	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	2	4/3/2020	SUPPLEMENT FOR EXPANSION	-$288,595
														Subtotal = $367,016

Issue Date FY: 2019 ( Subtotal = $348,750 )
2019	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/28/2019	NON-COMPETING CONTINUATION	$348,750
														Subtotal = $348,750

Issue Date FY: 2018 ( Subtotal = $698,297 )
2018	2018	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	4/19/2018	NON-COMPETING CONTINUATION	$34,875
2018	2018	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/15/2018	NON-COMPETING CONTINUATION	$313,875
2018	2018	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	9/14/2018	SUPPLEMENT FOR EXPANSION	$349,547
														Subtotal = $698,297

Issue Date FY: 2017 ( Subtotal = $348,750 )
2017	2017	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/18/2017	NEW	$348,750
														Subtotal = $348,750

Grand Total All Awards = $2,129,829

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Alpha-synuclein aggregation disrupts motility, synaptic transmission, and calcium signaling in the myenteric plexus of the rat colon

Award Number: R01DK108798

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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