Abstract
We reviewed recent progress in the pathogenesis of Parkinson's disease (PD) and familial forms of PD. PD is thought to be initiated by the interaction of mitochondrial respiratory failure and oxidative damage inducing protein aggregation, disturbance of axonal transport, and apoptosis. Regarding familial forms of PD, 11 forms have been mapped to certain chromosome loci. Mutations of the alpha-synuclein, UCH-L1, and LRRK2 genes cause autosomal dominant forms and mutations of parkin, PINK1, and DJ1 cause autosomal recessive forms. Alpha-synuclein also plays a crucial role in the pathogenesis of sporadic PD, insoluble aggregates are accumulated in neurons. Parkin, which is the causative gene for autosomal-recessive young-onset PD, shows a proteinubiquitin ligase activity. Accumulation of parkin-substrates may be responsible for nigral neuronal death in this form. PINK1 and DJ-1 are causative genes for other forms of autosomal-recessive young-onset PD. PINK1 is a mitochondrial protein and DJ-1 shows a strong anti-oxidant property suggesting the importance of mitochondrial dysfunction and oxidative damage in nigral neurodegeneration. LRRK2 is the causative gene for a form of autosomal dominant PD. LRRK2 protein has a protein kinase domain suggesting that abnormal phosphorylation of proteins is also important in the pathogenesis of nigra neuronal death.
