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Mechanisms of LRRK2 Mediated Neurotoxicity

Award Number: R01NS064934
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: 09/01/2010
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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View Award Description

Mechanisms of LRRK2 Mediated Neurotoxicity - Renewal Request for R01-NS064934 “Mechanisms of LRRK2 Neurotoxicity” Parkinson's disease (PD) and related Lewy body diseases represent common causes of Alzheimer's disease related dementias (ADRDs). According to the National Alzheimer's Project Act, Lewy body diseases affect more than one-million Americans, with onset of disease typically earlier in life than dementia caused by Alzheimer's disease. Tens of thousands of Americans harbor LRRK2 missense variants that can cause PD. Longitudinal studies show LRRK2 mutation carriers largely follow a typical course of motor and cognitive impairment over time, mirroring idiopathic disease. Post-mortem studies show that LRRK2 mutations are a potent genetic risk factor for the aggregation of tau and α-synuclein. LRRK2 variants associate with susceptibility to Crohn's disease and mycobacteria infection, highlighting LRRK2 function in immune cells. In the past project period, we observed a dual-activation phenomenon with intrinsic LRRK2 modifying α-synuclein aggregation in neurons, as well as high LRRK2 expression in myeloid cells recruited to the brain in disease models. In a novel enzymatic cycle that we intend to closely examine, LRRK2 mutations may increase cis LRRK2 kinase activity in autophosphorylation as well as trans phosphorylation of a small subset of Rab proteins. In our continued efforts to understand LRRK2 function in disease, we focus our attention to LRRK2- Rab substrate interactions. We propose a series of quantitative proximity labeling approaches to probe the inner catalytic core of LRRK2-Rab enzymatic cycling in disease-relevant cells. These experiments will be anchored through structure-function relationships identified by cryo-electron microscopy analysis of relevant protein complexes. We predict these experiments will shed light on how disparate pathogenic mutations in LRRK2 share a common final output in Rab hyper-phosphorylation. Further, we will explore how LRRK2 variants linked to protection from disease might affect the LRRK2-Rab catalytic cycle. Both LRRK2 and its Rab substrate constituency demonstrate some of the highest expression in subsets of myeloid cells in the immune system. In complement to our biochemical approach, we will dissect the role of LRRK2 in pro-inflammatory macrophages recruited to the brain in an AAV-α-synuclein mouse model. We anticipate mutant LRRK2 expression in peripheral immune cells will exacerbate deleterious neuroinflammation that correlates to dopaminergic neurodegeneration. We further predict that LRRK2 knockout in peripheral immune cells will attenuate pro-inflammatory responses in the brain and α-synuclein-induced loss of dopamine neurons. As several exploratory therapies that target LRRK2 have recently advanced through safety trials in the clinic, with project success, we predict our studies will further emphasize LRRK2-Rab signaling and peripheral immune responses in LRRK2-linked disease.


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 = $535,841 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	7/15/2025	NON-COMPETING CONTINUATION	$535,841
														Subtotal = $535,841

Issue Date FY: 2024 ( Subtotal = $519,765 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	7/10/2024	NON-COMPETING CONTINUATION	$519,765
														Subtotal = $519,765

Issue Date FY: 2023 ( Subtotal = $535,841 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	6/26/2023	NON-COMPETING CONTINUATION	$535,841
														Subtotal = $535,841

Issue Date FY: 2022 ( Subtotal = $535,841 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	13	6/23/2022	NON-COMPETING CONTINUATION	$535,841
2022	2021	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	12	1/10/2022	COMPETING CONTINUATION	$205,770
2022	2020	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	1/10/2022	SUPPLEMENT FOR EXPANSION	-$205,770
														Subtotal = $535,841

Issue Date FY: 2021 ( Subtotal = $535,841 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	12	6/23/2021	COMPETING CONTINUATION	$535,841
2021	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	6/18/2021	NON-COMPETING CONTINUATION	$0
2021	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	6/17/2021	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $535,841

Issue Date FY: 2020 ( Subtotal = $752,500 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	4/23/2020	NON-COMPETING CONTINUATION	$350,000
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	11	8/3/2020	SUPPLEMENT FOR EXPANSION	$402,500
2020	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	1/21/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $752,500

Issue Date FY: 2019 ( Subtotal = $350,000 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	10	2/28/2019	NON-COMPETING CONTINUATION	$350,000
2019	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	12/5/2018	NON-COMPETING CONTINUATION	-$115,948
2019	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	8	2/18/2019	NON-COMPETING CONTINUATION	-$1,992
2019	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	9	2/18/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,992
2019	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	12/6/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$115,948
														Subtotal = $350,000

Issue Date FY: 2018 ( Subtotal = $321,563 )
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	3/13/2018	NON-COMPETING CONTINUATION	$289,406
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	5/9/2018	NON-COMPETING CONTINUATION	$32,157
														Subtotal = $321,563

Issue Date FY: 2017 ( Subtotal = $321,563 )
2017	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	6/19/2017	NON-COMPETING CONTINUATION	$32,157
2017	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	3/20/2017	NON-COMPETING CONTINUATION	$289,406
														Subtotal = $321,563

Issue Date FY: 2016 ( Subtotal = $321,563 )
2016	2016	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	4/12/2016	COMPETING CONTINUATION	$321,563
														Subtotal = $321,563

Issue Date FY: 2014 ( Subtotal = $310,918 )
2014	2014	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	7/22/2014	NON-COMPETING CONTINUATION	$310,918
														Subtotal = $310,918

Issue Date FY: 2013 ( Subtotal = $303,067 )
2013	2013	UNIVERSITY OF ALABAMA AT BIRMINGHAM	UAB STATION, CBB 990	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/8/2013	NON-COMPETING CONTINUATION	$303,067
														Subtotal = $303,067

Issue Date FY: 2012 ( Subtotal = $314,059 )
2012	2012	UNIVERSITY OF ALABAMA AT BIRMINGHAM	UAB STATION, CBB 990	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/2/2012	NON-COMPETING CONTINUATION	$314,059
														Subtotal = $314,059

Issue Date FY: 2011 ( Subtotal = $314,059 )
2011	2011	UNIVERSITY OF ALABAMA AT BIRMINGHAM	UAB STATION, CBB 990	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/24/2011	NON-COMPETING CONTINUATION	$314,059
														Subtotal = $314,059

Issue Date FY: 2010 ( Subtotal = $320,469 )
2010	2010	UNIVERSITY OF ALABAMA AT BIRMINGHAM	UAB STATION, CBB 990	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/11/2010	NEW	$320,469
														Subtotal = $320,469

Grand Total All Awards = $6,292,890

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Mechanisms of LRRK2 Mediated Neurotoxicity

Award Number: R01NS064934

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: 09/01/2010

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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