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Impact of Dysfunctional BDNF on Dopamine Terminal Remodeling in the Parkinsonian Striatum

Award Number: R01NS105826
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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Impact of Dysfunctional BDNF on Dopamine Terminal Remodeling in the Parkinsonian Striatum - While there are a number of therapeutic options for individuals with Parkinson's disease (PD) these therapies do not work uniformly well in all patients. Indeed, a recent retrospective analysis of the ELLDOPA study reported that early-stage PD subjects receiving equivalent levodopa doses experienced a magnitude of response ranging from a 100% improvement to a 242% worsening as assessed with the United Parkinson's Disease Rating Scale part III (UPDRS-III, motor subscore). This example underscores the incredible heterogeneity in clinical response to standard-of-care anti-parkinsonian therapy, even when disease severity is taken into account. Similar findings have been reported over the past several decades for the experimental regenerative approach of neural grafting. While some PD patients have shown marked and lasting benefit following engraftment of primary dopamine (DA) neurons, many have also shown no or limited benefit. Recent preclinical data in aged parkinsonian rats together with that from two milestone clinical reports provide compelling and sobering data demonstrating that even when robust survival of grafted DA neurons and extensive neurite outgrowth is achieved, obstacle(s) remain that interfere with functional circuit restoration within the aged, parkinsonian brain. As clinical grafting trials are reemerging, it remains uncertain what specific risk factors negatively impact clinical responsiveness to DA terminal remodeling. In attempt to deconstructing the complexity of PD and response to therapy, we recently identified one candidate genetic variant, with prevalence of up to 40% in the human population, which may prove useful in this regard; specifically, a functional single nucleotide polymorphism (SNP) rs6265 in the Bdnf gene for brain-derived neurotrophic factor (BDNF) that results in dysfunctional BDNF release. We have recently observed diminished therapeutic efficacy of oral levodopa in two distinct cohorts of PD patients with this SNP risk allele. In the current application we propose to test the hypothesis that this risk allele also underlies the variability in clinical response to DA neuron grafting in PD patients. Specifically, we hypothesize that BDNF is an unrecognized contributor to the discordant finding of abundant survival of grafted DA neurons and lack of behavioral efficacy reported in a subpopulation of PD patients and in association with normal aging in parkinsonian rats. In this application we propose three Specific Aims to test the overarching hypothesis that impaired BDNF signaling, either through this common SNP and/or advanced age, is a key factor in limiting functional DA terminal remodeling. Toward this end, we have generated a knock-in rat model of the human rs6265 BDNF variant and propose to use this novel tool to characterize its effects and interaction with aging and DA-depletion on the function and synaptic integration of new DA terminals in the parkinsonian striatum using neural grafting as a model system.


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 = $0 )
2024	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $324,625 )
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	2/1/2023	NON-COMPETING CONTINUATION	$32,463
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/13/2022	NON-COMPETING CONTINUATION	$292,162
														Subtotal = $324,625

Issue Date FY: 2022 ( Subtotal = $347,350 )
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/6/2022	NON-COMPETING CONTINUATION	$312,614
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	3/25/2022	NON-COMPETING CONTINUATION	$34,736
														Subtotal = $347,350

Issue Date FY: 2021 ( Subtotal = $352,660 )
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	1/18/2021	NON-COMPETING CONTINUATION	$35,267
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/10/2020	NON-COMPETING CONTINUATION	$317,393
														Subtotal = $352,660

Issue Date FY: 2020 ( Subtotal = $404,677 )
2020	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/9/2019	NON-COMPETING CONTINUATION	$364,209
2020	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	2/10/2020	NON-COMPETING CONTINUATION	$40,468
														Subtotal = $404,677

Issue Date FY: 2019 ( Subtotal = $355,680 )
2019	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/14/2018	NEW	$355,680
														Subtotal = $355,680

Grand Total All Awards = $1,784,992

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Impact of Dysfunctional BDNF on Dopamine Terminal Remodeling in the Parkinsonian Striatum

Award Number: R01NS105826

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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