Genetic Factors in Parkinsons Disease and Potential Therapeutic Targets

Jian      Feng

Abstract

Parkinsons disease is a neurodegenerative movement disorder caused by a combination of environmental and genetic factors. Recent human genetic studies have identified five genes that are linked to Parkinsons disease (PD): α-synuclein, parkin, UCH-L1, DJ-1 and NR4A2. Among these genes, a variety of mutations in the human parkin locus have been found in many PD cases, both familial and sporadic. Parkin appears to be the most prevalent genetic factor in PD. It encodes for a protein-ubiquitin E3 ligase, whose loss-offunction mutations cause specific degeneration of dopamine (DA) neurons in substantia nigra in human patients. The accumulation of parkin substrates is thought to be the key factor in the selective death of DA neurons. Rapid progress in the identification of these substrates and the generation of genetic animal models has produced a plethora of knowledge about the biological function of parkin and its role in PD. These studies also offer novel pharmacological targets for the development of more selective therapeutic strategies. In this review, I will summarize results from this fast expanding field and discuss their potential implication in the treatment of Parkinsons disease.

Keywords: parkin, synuclein, parkinson's disease, ubiquitination, misfolding, microtubule, dopamine, tubulin