Mutations in the PINK1 gene are a rare genetic cause of autosomal recessive Parkinson's disease (PD). The PINK1 protein is either absent or appears to be functionally inactive in the families in which the mutations have been identified. Thus, mutations in the PINK1 gene probably cause PD through a loss of function. It is difficult at this juncture to fully appreciate how mutations in the PINK1 gene cause PD, as its function is largely unknown. PINK1 was identified as a mitochondrial enriched protein kinase. Loss of function of PINK1 increases cellular susceptibility to oxidative stress. How a loss of function of P1NK1 leads to loss of DA neurons and PD awaits further study. We propose to generate and characterize PINK1 knockout mice to formally test the hypothesis that the absence of PINK1 function is the cause of PD due to PINK1 mutations. Accordingly experiments are proposed to further characterize the role of PINK1 in the pathogenesis of PD.
In Specific Aim #1 we will develop and characterize PINK1 knockout mice.
In Specific Aim #2 we will we will evaluate the sensitivity of PINK1 knockouts to environmental toxins including MPTP-induced dopaminergic cell death.
In Specific Aim #3 we will determine whether PINK1, Parkin and/or DJ-1 participate in a common pathogenic pathway by crossing PINK1 knockouts with Parkin and DJ-1 knockouts. Development and characterization of PINK1 knockouts, understanding the relationship of PINK1 and mitochondrial function in the pathogenesis of PD may provide insight into the molecular mechanisms by which these gene products induce neuronal damage and may provide novel therapeutics and targets to prevent the toxic effects of this familial associated gene in the degenerative process of PD.
| Savitt, Joseph M; Dawson, Valina L; Dawson, Ted M (2006) Diagnosis and treatment of Parkinson disease: molecules to medicine. J Clin Invest 116:1744-54 |
