Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by widespread neurodegeneration in the brain with profound loss of dopamine-containing neurons of the substantia nigra pars compacta. While majority of PD cases are sporadic, inherited mutations account for approximately 10% of PD cases. Existing evidence implicates a major role for stress activated protein kinases in the pathogenesis of PD. Activation of a neuronal specific c-jun N-terminal kinase-3 (JNK3), followed by recruitment to mitochondria, is associated with irreversible neurodegeneration. The mechanisms underlying this process however remain poorly understood. We have cloned a neuron-specific mitochondrial protein, called MyD88-5, which is enriched in Lewy bodies from brains of postmortem PD patients and in pathologically affected regions of the CNS in a mouse model of 1-synuclein induced PD. We showed that expression of MyD88-5 in vitro led to recruitment of JNK3 from the cytosol to mitochondria and that MyD88-5 knockout mice were resistant to dopaminergic neurodegeneration caused by parkinsonian neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). We therefore hypothesize that MyD88-5 may link JNK3 to mitochondria-dependent cell death.
Three specific aims are proposed to test this hypothesis.
Aim 1 will examine the role of MyD88-5 in activating JNK3 and mediating dopaminergic cell death in MPTP-induced PD using MyD88-5 knockout mice.
Aim 2 will examine the role of MyD88-5 in the pathogenesis of mutant human A53T 1-synuclein-induced PD by expressing this transgene in nigral dopaminergic neurons of MyD88-5 knockout mice, or by generating and testing A53T 1- synuclein transgenic/MyD88-5-null mice.
Aim 3 will dissect the role of MyD88-5 in modulating basal mitochondrial physiology and function that are important in the PD development in both MPTP- and in 1-synuclein-induced PD using MyD88-5-null mouse. Together, these studies should increase knowledge of MyD88-5-dependent cell damage pathways associated with neurodegeneration in PD and help identify new therapeutic target(s) for the treatment of PD.

Public Health Relevance

This study propose to examine the role of a newly discovered brain mitochondrial protein, MyD88-5, in the onset and development of Parkinson's disease (PD) using the MPTP-neurotoxin and mutant human 1-synuclein mouse models. The study will enrich and refine our understanding of MyD88-5-dependent cell damage pathways observed in PD and identify new target(s) for intervention in PD pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS060885-05
Application #
8305587
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sieber, Beth-Anne
Project Start
2008-07-16
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$314,229
Indirect Cost
$99,854
Name
Georgia Regents University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
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Yin, Fangfang; Dumont, Magali; Banerjee, Rebecca et al. (2010) Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia. FASEB J 24:4639-47

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