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LRRK2 Enzymatic Mechanisms of Neurodegeneration in Parkinson's Disease

Award Number: R01NS120489
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: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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LRRK2 Enzymatic Mechanisms of Neurodegeneration in Parkinson's Disease - Project Summary Parkinson's disease (PD) is a progressive neurodegenerative movement disorder caused primarily by the degeneration of dopaminergic neurons in the substantia nigra. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant PD, and LRRK2 coding and non-coding variants are associated with risk of sporadic PD. LRRK2 has emerged has an important therapeutic target for treating PD and therefore it is critical to understand the key mechanisms underlying disease-linked mutations. LRRK2 is a large multi-domain protein containing Ras-of-Complex (Roc) GTPase and protein kinase enzymatic domains separated by a C-terminal-of-Roc (COR) domain. GTP-binding via the Roc domain is critical for normal kinase activity. Familial LRRK2 mutations cluster within the Roc (R1441C/G/H), COR (Y1699C) and kinase (G2019S, I2020T) domains where they commonly enhance the phosphorylation of a subset of Rab GTPase substrates in cells. Roc-COR domain mutations act indirectly on kinase activity by impairing GTP hydrolysis and promoting the GTP-bound `on' state. The GTPase and kinase domains represent promising targets for inhibiting LRRK2. While familial LRRK2 mutations share the capacity to induce neuronal damage in cultured cells, their effects in animal models are less certain due to a lack of robust neurodegenerative phenotypes. In addition, how the two enzymatic activities contribute to neuronal damage in vivo induced by familial LRRK2 mutations is poorly understood. We have recently developed an adenoviral-mediated gene transfer model in adult rats where G2019S LRRK2 induces nigrostriatal pathway dopaminergic neurodegeneration through a kinase-dependent mechanism. In the present application, we propose to exploit this robust and rapid rodent model to determine whether kinase activity is commonly required for neurodegeneration induced by familial mutations (R1441C, Y1699C and G2019S) or PD risk variants (G2385R) in LRRK2 by genetic and pharmacological kinase inhibition (Aim 1.1). The contribution of Rab phosphorylation to neuronal damage induced by mutant LRRK2 is not known. We will determine the neuroprotective effects of globally reducing Rab phosphorylation in mutant LRRK2 neuronal and adenoviral rat models by overexpressing a novel Rab-specific phosphatase, PPM1H (Aim 1.2). Knockdown of PPM1H will explore whether increasing Rab phosphorylation is sufficient to phenocopy the neurotoxic effects of mutant LRRK2. Our studies will further explore whether genetically modulating GTPase activity can provide a common neuroprotective mechanism against different familial LRRK2 mutations in rodents (Aim 2.1). In particular, we will evaluate hypothesis-testing mutations that increase GTP hydrolysis and promote the GDP-bound `off' state of LRRK2. Finally, we will explore how the native interactome of LRRK2 in neurons is regulated by the GTPase cycle to identify novel protein targets that interact with LRRK2 in its GDP- or GTP- bound states (Aim 2.2). Our studies will provide critical mechanistic insight into how GTPase and kinase activity regulate LRRK2-mediated neurodegeneration, and will be important for therapeutic discovery efforts for 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: 2025 ( Subtotal = $427,500 )
2025	2025	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/13/2024	NON-COMPETING CONTINUATION	$427,500
														Subtotal = $427,500

Issue Date FY: 2024 ( Subtotal = $460,750 )
2024	2024	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	5/3/2024	NON-COMPETING CONTINUATION	$33,250
2024	2024	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/14/2023	NON-COMPETING CONTINUATION	$427,500
														Subtotal = $460,750

Issue Date FY: 2023 ( Subtotal = $475,000 )
2023	2023	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/14/2023	NON-COMPETING CONTINUATION	$475,000
2023	2022	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	10/25/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $475,000

Issue Date FY: 2022 ( Subtotal = $475,000 )
2022	2022	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/28/2022	NON-COMPETING CONTINUATION	$47,500
2022	2022	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/6/2021	NON-COMPETING CONTINUATION	$427,500
2022	2022	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	8/24/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $475,000

Issue Date FY: 2021 ( Subtotal = $475,000 )
2021	2021	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	9/9/2021	NEW	$0
2021	2021	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/20/2020	NEW	$475,000
														Subtotal = $475,000

Grand Total All Awards = $2,313,250

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LRRK2 Enzymatic Mechanisms of Neurodegeneration in Parkinson's Disease

Award Number: R01NS120489

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: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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