Parkinson's disease (PD), the second most common neurodegenerative disease, is a progressive neurological condition that affects substantia nigra (SN) in the midbrain region. The etiology of the disease is not completely understood, however, inherited risk factors and environmental toxins are considered likely causes. PD and certain other dementias are associated with brain lesions known as Lewy bodies, which contain a-synuclein (a-Syn) as the major component. Mutations in the a-Syn gene have been linked with certain familial forms of PD. It has been suggested that mutations in a-Syn (Ala⁵³ to Thr⁵³ and Ala³⁰ to Pro³⁰) may cause a conformational change that renders a-Syn more prone to self-aggregation and deposition in Lewy bodies. Expression of mutant a-Syn in dopaminergic neurons impairs synaptic vesicle formation, increases cytoplasmic levels of dopamine, and increases superoxide radicals in the cytoplasm, which lead to oxidative stress and misfolding of a-Syn. Various mutations in yet another gene, the Parkin gene, are reported in early autosomal-recessive form of PD, however, these mutations do not generate Lewy bodies. The Parkin gene's product is an E3 ubiquitin ligase. Known substrates of Parkin include Pael-R (Parkin-associated endothelin-receptor-like receptor), CDCrel-1 (cell-division-control-related protein 1), Synphilin-1, and a glycosylated form of a-Syn (a-SP22). Only the glycosylated form,a-SP22, is ubiquitinated by Parkin. Unfolding of Pael-R makes it insoluble and allows it to accumulate in the endoplasmic reticulum. Ubiquitination of Pael-R by Parkin leads to its degradation in the proteasome, however, failure to ubiquitinate it leads to the death of the neuron.

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