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.
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.
|Ahuja, Manuj; Ammal Kaidery, Navneet; Yang, Lichuan et al. (2016) Distinct Nrf2 Signaling Mechanisms of Fumaric Acid Esters and Their Role in Neuroprotection against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Experimental Parkinson's-Like Disease. J Neurosci 36:6332-51|
|Wakade, Chandramohan; Chong, Raymond; Bradley, Eric et al. (2014) Upregulation of GPR109A in Parkinson's disease. PLoS One 9:e109818|
|Stack, Cliona; Jainuddin, Shari; Elipenahli, Ceyhan et al. (2014) Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity. Hum Mol Genet 23:3716-32|
|Hou, Ying-Ju; Banerjee, Rebecca; Thomas, Bobby et al. (2013) SARM is required for neuronal injury and cytokine production in response to central nervous system viral infection. J Immunol 191:875-83|
|Ammal Kaidery, Navneet; Tarannum, Shaista; Thomas, Bobby (2013) Epigenetic landscape of Parkinson's disease: emerging role in disease mechanisms and therapeutic modalities. Neurotherapeutics 10:698-708|
|Kaidery, Navneet Ammal; Banerjee, Rebecca; Yang, Lichuan et al. (2013) Targeting Nrf2-mediated gene transcription by extremely potent synthetic triterpenoids attenuate dopaminergic neurotoxicity in the MPTP mouse model of Parkinson's disease. Antioxid Redox Signal 18:139-57|
|Thomas, Bobby; Banerjee, Rebecca; Starkova, Natalia N et al. (2012) Mitochondrial permeability transition pore component cyclophilin D distinguishes nigrostriatal dopaminergic death paradigms in the MPTP mouse model of Parkinson's disease. Antioxid Redox Signal 16:855-68|
|Thomas, Bobby; Mandir, Allen S; West, Neva et al. (2011) Resistance to MPTP-neurotoxicity in Î±-synuclein knockout mice is complemented by human Î±-synuclein and associated with increased Î²-synuclein and Akt activation. PLoS One 6:e16706|
|Ramonet, David; Daher, JoÃ£o Paulo L; Lin, Brian M et al. (2011) Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS One 6:e18568|
|Chinopoulos, Christos; Zhang, Steven F; Thomas, Bobby et al. (2011) Isolation and functional assessment of mitochondria from small amounts of mouse brain tissue. Methods Mol Biol 793:311-24|
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