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Role of presynaptic targeting of alpha-synuclein in the pathogenesis of Parkinson's Disease and Dementia with Lewy Bodies

Award Number: R01NS102257
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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Parkinson’s Disease (PD) and Dementia with Lewy Bodies (DLB) are characterized by cytoplasmic inclusions called Lewy Bodies and Lewy Neurites which are composed primarily of a-synuclein (a-syn). Multiple lines of evidence suggest that these inclusions contribute to disease pathogenesis. Thus, preventing a-syn aggregation is a critical therapeutic target for preventing disease progression. Normally, a-syn resides at the presynaptic terminal, preferentially associates with synaptic vesicles, and interaction of a-syn with membranes inhibit its aggregation. Our proposed study seeks to determine how presynaptic targeting of a-syn prevents it from converting to a pathologic, aggregation prone form and how PD risk factors disrupt the normal localization of a-syn and increase its propensity to forming inclusions. Mutations in leucine rich repeat kinase (LRRK2) are the most common cause of familial Parkinson’s disease. We showed that the G2019S-LRRK2 mutations increase the formation of a-syn inclusions and that LRRK2 kinase inhibitors reduce inclusion formation, but the mechanisms by which LRRK2 controls the propensity of a-syn to form aggregates is unknown. Although current research focuses on the role of LRRK2 in degradative organelles, LRRK2 has also been functionally implicated at the presynaptic terminal and may play a role in a-syn presynaptic membrane targeting. Recently, a subset of Rab GTPases was identified as LRRK2 substrates. Rabs control distinct steps in membrane trafficking pathways in the cell. Ten years ago, the Lindquist lab identified the same Rabs (that were recently shown to be phosphorylated by LRRK2) as protective in models of a-syn toxicity. We will determine if Rabs phosphorylated by LRRK2 enhance presynaptic targeting of a-syn and prevent a-syn inclusion formation. Because inclusions localize to multiple brain regions in PD and DLB, we will inject fibrils into the mouse striatum which produces inclusions in the substantia nigra pars compacta (SNpc), cortex, and amygdala. In Aim 1, we will determine the extent to which select Rab isoforms influence a-syn presynaptic targeting using novel AAV vectors to increase Rab expression in the brain or use antisense oligonucleotides (ASOs) to reduce Rab levels. Immunohistochemistry and biochemistry will be used to determine if expression of these Rabs in vivo prevents formation of fibril-induced inclusions in multiple brain regions, and loss of dopamine neurons in the SNpc. In Aim 2, we will identify the Rab effectors in neurons that specify targeting of vesicles containing a- syn cargo to the presynaptic terminal. Finally, in Aim 3, we will determine if LRRK2 kinase activity prevents presynaptic targeting of a-syn and if the mislocalization of a-syn in the cell increases its propensity to form inclusions. We will also determine the extent to which LRRK2 kinase inhibitors and ASOs in preclinical development enhance presynaptic targeting of a-syn. These studies will open up new research avenues for understanding how factors and genes that cause PD and DLB increase the propensity of a-syn to aggregate, and how to therapeutically target LRRK2 and downstream effectors to prevent the progression of 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: 2024 ( Subtotal = -$22,149 )
2024	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/15/2023	NON-COMPETING CONTINUATION	-$22,149
														Subtotal = -$22,149

Issue Date FY: 2022 ( Subtotal = $371,250 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/7/2022	NON-COMPETING CONTINUATION	$334,125
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	3/24/2022	NON-COMPETING CONTINUATION	$37,125
														Subtotal = $371,250

Issue Date FY: 2021 ( Subtotal = $371,250 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/2/2021	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2020 ( Subtotal = $371,250 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/18/2020	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2019 ( Subtotal = $371,250 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/5/2019	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2018 ( Subtotal = $371,250 )
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	1	5/1/2018	NEW	$324,844
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	1	6/4/2018	NEW	$46,406
														Subtotal = $371,250

Grand Total All Awards = $1,834,101

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Role of presynaptic targeting of alpha-synuclein in the pathogenesis of Parkinson's Disease and Dementia with Lewy Bodies

Award Number: R01NS102257

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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