Parkinson's disease (PD) is a frequent cause of neurodegeneration, disability and premature mortality in older adults. Loss of dopaminergic neurons in the substantia nigra is the primary neuropathological hallmark of PD. There are currently no treatments proven to slow down the progressive nigral cell loss in PD, which causes increasing severity of the clinical symptoms. The recent linking of human mutations in genes such as Parkin, DJ-1, and PINK1 to recessively inherited forms of PD provides new opportunities to discover pathogenic mechanisms and to develop and test neuroprotective therapies in animal models with nigral cell loss based on mechanisms physiologically relevant to human parkinsonism. We have pursued this strategy for over a decade using knockout (KO) mice. For unknown reasons, without further insult, Parkin KO, DJ-1 KO and PINK1 KO mice do not reproduce the nigral cell loss that occurs in humans bearing loss-of-function mutations in these genes. The lack of nigral cell loss precludes using nigral cell loss as an outcome measure to directly test potential pathogenic mechanisms and neuroprotective strategies in Parkin KO, DJ-1 KO or PINK1 KO mice. Recently developed DJ-1 KO rats show age-dependent nigral cell loss with a full complement of dopamine neurons at ages 4 months and 6 months but greater than 50% loss by age 8 months. The age-dependent nigral neuron loss in DJ-1 KO rats makes it possible for the first time to test candidate pathogenic mechanisms directly in a mammalian brain that reproduces this central neuropathological feature of PD. We propose to use DJ-1 KO rats to achieve the following specific aims based on previous in vitro studies of DJ-1 function and pathogenic mechanisms of DJ-1 mutations: 1) To determine whether DJ-1 expression in neurons, astrocytes or both is required to prevent age-dependent loss of nigral dopamine neurons in rats and 2) To determine whether DJ-1 cysteine 106 is required for DJ-1 in vivo to prevent nigral cell loss. We expect to contribute a systematic characterization of DJ-1 KO rats as an apt test bed for therapeutic development by testing the principal hypothesis that cysteine 106 is required for DJ-1 to prevent nigral cell loss in DJ-1 KO rats and the second main hypothesis that DJ-1 expression in astrocytes is required to prevent nigral cell loss in DJ-1 KO rats. The use of this novel rat model of nigral cell loss is innovative and the proposal will significantly impact the understanding of PD by shifting emphasis to disease mechanisms present in PD brain tissue selected for their strong therapeutic potential. We expect that our findings will be broadly applicable to the development of neuroprotective therapies for familial and sporadic PD as well as other neurodegenerative diseases.

Public Health Relevance

Parkinson's disease (PD), which is caused by unknown factors or by mutations in genes such as DJ-1, is intractable and its symptoms can only be lessened by life-long a palliative effort, which constitutes an important health problem. Testing the mechanisms connecting progressive nigral neuronal loss to molecular events in PD tissue fulfills the NIH mission by uncovering new fundamental aspects of brain function and by facilitating the development of potential therapies aimed at brain cell protection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS082888-01A1
Application #
8701758
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sieber, Beth-Anne
Project Start
2014-02-15
Project End
2016-01-31
Budget Start
2014-02-15
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$238,500
Indirect Cost
$88,500
Name
University of Texas Sw Medical Center Dallas
Department
Neurology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390