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Combining synucleinopathy and mitochondrial deficits in a novel mouse model of Parkinsons disease

Award Number: R33NS106078
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

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The lack of animal models recreating the progressive pathology characteristic of Parkinson’s disease (PD) hinders the development of effective disease-modifying therapies. Thus, the goal of this project is to generate a new animal PD model that supports the development of such therapies. Clinical data revealed that axon terminal failure and “dying back” of dopaminergic neurons likely precede loss of substantia nigra cell bodies by many years in PD. This protracted process is not replicated in the acute toxin-induced animal models of PD, providing one possible explanation for the low predictive power of these models. The heterozygous deletion of the engrailed 1 gene in mice (En1+/–) results in axon terminal dysfunction and degeneration eventually leading to protracted loss of nigral dopaminergic neurons. This process causes striatal dopamine deficiency that leads to motor impairment. Furthermore, these changes are associated with mitochondrial deficits akin to those observed in some PD patients. Despite all the advantages that the En1+/– mouse model represents, it lacks a-syn aggregation. Thus, we hypothesize that mitochondrial deficits (due to heterozygous loss of En1) combined with bilateral injections of pathogenic a-syn fibrils (PFFs) will synergistically generate a highly relevant PD model – En1/SYN. We further predict that the En1/SYN model will exhibit a comprehensive set of PD-relevant behavioral deficits (both motor and non-motor) and will mimic PD neuropathology. This approach is innovative in combining, in mice, key aspects of PD, the susceptibility of the dopaminergic system, a-syn and the multifactorial nature of the etiology of PD. Supporting our hypothesis, our preliminary data show that PFFs-induced a-syn pathology is significantly exacerbated by the loss of En1. There are two major goals in this project: (1) We will trigger PFFs-induced a-syn pathology bilaterally by injecting pathogenic a-synuclein into both striata. By triggering the pathology on both sides of the brain the new mouse model is expected to induce robust motor, and more importantly cognitive deficits. We will bilaterally inject recombinant fibrillar a-syn (provided by Dr. Jiyan Ma), measure the development of a-syn-associated pathology, and then assess motor and non-motor function of mice at different time points; (2) We will validate the En1/SYN model as a model of PD, by comparing the features of our model to human PD in long-term experiments, as well as by testing if the gold-standard PD treatment L-DOPA reverses motor deficits induced by loss of nigral dopamine neurons and widespread a-syn aggregation. Our research is expected to generate a powerful tool, which can accelerate the development of symptomatic and/or disease-modifying therapies to treat motor and non-motor 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 = -$39,099 )
2024	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	3	2/21/2024	EXTENSION WITH OR WITHOUT FUNDS	-$39,099
														Subtotal = -$39,099

Issue Date FY: 2023 ( Subtotal = $0 )
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	3	12/21/2022	EXTENSION WITH OR WITHOUT FUNDS	$0
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	001	3	1/23/2023	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $436,098 )
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	003	3	6/15/2022	EXTENSION WITH OR WITHOUT FUNDS	$0
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	3	12/20/2021	EXTENSION WITH OR WITHOUT FUNDS	$436,098
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	3	1/27/2022	EXTENSION WITH OR WITHOUT FUNDS	$0
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	3	2/8/2022	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $436,098

Grand Total All Awards = $396,999

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Combining synucleinopathy and mitochondrial deficits in a novel mouse model of Parkinsons disease

Award Number: R33NS106078

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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