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Mouse model studies of TMEM230-linked Parkinson's disease

Award Number: R01NS099623
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: 09/30/2016
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Mouse model studies of TMEM230-linked Parkinson's disease - Through our previous work funded by the American Parkinson Disease Association and NINDS, we have discovered a new Parkinson’s disease (PD) genetic locus on the short arm of chromosome 20, and identified a new PD gene, TMEM230. TMEM230 encodes a transmembrane protein of secretory and recycling vesicles, including synaptic vesicles in neurons. TMEM230 is the first transmembrane protein of synaptic vesicles identified in PD to date. Our findings, therefore, directly point to the dysfunction of synaptic vesicles in the pathogenesis of PD. The precise physiological functions of TMEM230, and pathogenic mechanism of the TMEM230-mediated PD remain unclear. Based on the molecular features of TMEM230, and its relationship with synaptic vesicle and endosomal markers tested in our study, we hypothesize that TMEM230 is a trafficking protein of synaptic vesicles, and it may function in synaptic vesicle biogenesis, exocytosis, endocytosis and recycling, and synaptic transmission in neurons. But it remains to be determine where in the subcellular compartments and what functions that TMEM230 plays. In the previous funding cycle, we identified TMEM230 as an endocytic cargo protein that binds to the medium subunit (AP2M1) of adaptor protein 2 complex (AP2) to promote AP2-dependent clathrin-mediated endocytosis; whereas, PD-linked mutations affect this process and impair synaptic vesicle recycling, more specifically, by affecting budding from presynaptic membrane to form new AP2/clathrin-coated recycling vesicles. In this application, we propose three specific aims to determine the physiological function of TMEM230, especially the functional motifs for TMEM230 to bind to AP2M1, and the pathogenic mechanism underlying TMEM230-linked PD. We propose to develop a total of six TMEM230 mouse models in specific aim 1, to perform phenotypical, pathological and biochemical characterization in specific aim 2, and to perform neurophysiological characterization of nigrostriatal pathway in these mouse models in specific aim 3. SV recycling deficits have emerged as a convergent pathogenic pathway underlying PD pathogenesis. There is evidence that LRRK2, auxilin and synaptojanin 1 affect clathrin uncoating; and VPS35 may impair retromer- TGN trafficking. TMEM230 appears to affect a distinct step in SV recycling i.e., budding from the presynaptic membrane to form new AP2/clathrin-coated recycling SVs. A number of important issues remains to be addressed. Based on our resources and expertise, we propose to address some of these issues using relevant mouse models in this application. Successful completion of the proposed studies will provide essential information to understand the physiological function of TMEM230 and the pathogenic mechanism underlying TMEM230-linked PD. Moreover, since TMEM230-linked PD shows clinical and pathological features compatible with those in classical PD, the outcomes from this study may also have important implications in understanding the pathogenic mechanisms in other forms of PD, including sporadic 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: 2026 ( Subtotal = $420,940 )
2026	2026	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	12/16/2025	NON-COMPETING CONTINUATION	$420,940
														Subtotal = $420,940

Issue Date FY: 2025 ( Subtotal = $450,079 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	11/25/2024	NON-COMPETING CONTINUATION	$450,079
														Subtotal = $450,079

Issue Date FY: 2024 ( Subtotal = $485,086 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	11/17/2023	NON-COMPETING CONTINUATION	$450,079
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	8	4/24/2024	NON-COMPETING CONTINUATION	$35,007
2024	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	10/30/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $485,086

Issue Date FY: 2023 ( Subtotal = $500,086 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	2/10/2023	NON-COMPETING CONTINUATION	$500,086
														Subtotal = $500,086

Issue Date FY: 2022 ( Subtotal = $518,815 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	2/25/2022	COMPETING CONTINUATION	$1,999
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	11/25/2021	COMPETING CONTINUATION	$518,815
2022	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	2/25/2022	NON-COMPETING CONTINUATION	-$1,999
														Subtotal = $518,815

Issue Date FY: 2020 ( Subtotal = $442,758 )
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/6/2020	NON-COMPETING CONTINUATION	$442,758
														Subtotal = $442,758

Issue Date FY: 2019 ( Subtotal = $442,758 )
2019	2019	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/24/2019	NON-COMPETING CONTINUATION	$442,758
														Subtotal = $442,758

Issue Date FY: 2018 ( Subtotal = $442,758 )
2018	2018	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/25/2018	NON-COMPETING CONTINUATION	$442,758
														Subtotal = $442,758

Issue Date FY: 2017 ( Subtotal = $442,758 )
2017	2017	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/14/2017	NON-COMPETING CONTINUATION	$442,758
														Subtotal = $442,758

Issue Date FY: 2016 ( Subtotal = $460,656 )
2016	2016	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/26/2016	NEW	$460,656
														Subtotal = $460,656

Grand Total All Awards = $4,606,694

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Mouse model studies of TMEM230-linked Parkinson's disease

Award Number: R01NS099623

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: 09/30/2016

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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