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Age-related deficits in trophic support of dopamine neurons in preclinical models of Parkinson's disease

Award Number: R01NS147081
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: 04/24/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Age-related deficits in trophic support of dopamine neurons in preclinical models of Parkinson's disease - PROJECT SUMMARY The progressive loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) in Parkinson’s disease (PD) occurs over several years. Identifying early mechanisms of this degeneration can aid in developing neuroprotective treatments, as current therapies are given only after significant loss of nigrostriatal function. One common monogenic form of late-onset PD is caused by mutations in the leucine-rich repeat kinase 2 (LRRK2) gene, leading to a hyperactive kinase. LRRK2-medated PD resembles idiopathic PD, showing similar pathological features, including age-dependent loss of DA neurons in the SNc Carriers of LRRK2 mutations are suitable candidates for early therapeutic interventions. However, currently no unifying hypothesis explains how LRRK2 contributes to DA neuron dysfunction. In a genetic mouse model with the common LRRK2 mutation (LRRK2G2019S), we found disruptions in release sites of DA axons and loss of cilia in striatal cholinergic and parvalbumin interneurons (CINs and PVINs, respectively). Therefore, we hypothesize that these cellular phenotypes may be linked through a signaling loop involving the glial cell line–derived neurotrophic factor (GDNF) and neurturin pathways, which support and maintain DA neurons. This study will examine cell-type-specific alterations in LRRK2G2019S mice to investigate how LRRK2 mutation affects this neuroprotective signaling pathway and DA neuron health at early stages of the disease. Aim 1 will investigate LRRK2-mediated disruptions at DA release sites in vulnerable DA neuron subpopulations in PD. It will also assess the age dependency and regional pattern of cilia loss in CINs and PVINs. We propose that impaired release machinery decreases key signaling molecules like sonic hedgehog (Shh) in the nigrostriatal pathway, reducing neurotrophin production by striatal interneurons. Age-related cilia loss exacerbates the issue, further diminishing neurotrophin-induced intracellular signaling. Aim 1 will also define the molecular mechanisms underlying these cellular dysfunctions related to LRRK2 mutations. Aim 2 will investigate how LRRK2-linked cellular disruptions affect key components of neurotrophic signaling and result in decreased DA neuron markers and ultimately DA neuron loss in a dual hit model of PD. To enhance the therapeutic impact of our findings, we will test whether clinically relevant LRRK2 inhibitors can reverse these disruptions and propose novel therapeutic avenues to restore DA neuron health. Our study will use advanced genetic models, molecular tools, and biochemical methods to explore PD pathophysiology, directly linking LRRK2 to DA neuron health. With the clinical development of small molecule LRRK2 kinase inhibitors, our findings will help identify new targets and pathways to slow disease progression.


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 = $566,529 )
2026	2026	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/28/2026	NEW	$566,529
														Subtotal = $566,529

Grand Total All Awards = $566,529

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Age-related deficits in trophic support of dopamine neurons in preclinical models of Parkinson's disease

Award Number: R01NS147081

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: 04/24/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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