Controlling the mass action of alpha-synuclein in Parkinson's disease.
Parkinson's disease (PD) is an age-related neurodegenerative disease with unknown etiology. Growing evidence from genetic, pathologic, animal modeling, and biochemical studies strongly support the theory that abnormal aggregation of alpha-synuclein plays a critical role in the pathogenesis of PD. Protein aggregation is an alternative folding process that competes with the native folding pathway. Whether or not a protein is subject to the aggregation process is determined by the concentration of the protein as well as thermodynamic properties inherent to each polypeptide. An increase in cellular concentration of alpha-synuclein has been associated with the disease in both familial and sporadic forms of PD. Thus, maintenance of the intraneuronal steady state levels of alpha-synuclein below the critical concentration is a key challenge neuronal cells are facing. Expression of the alpha-synuclein gene is under the control of environmental factors and aging, the two best-established risk factors for PD. Studies also suggest that the degradation of this protein is mediated by proteasomal and autophagic pathways, which are two mechanisms that are related to the pathogenesis of PD. Recently, vesicle-mediated exocytosis has been suggested as a novel mechanism for disposal of neuronal alpha-synuclein. Relocalization of the protein to specific compartments may be another method for increasing its local concentration. Regulation of the neuronal steady state levels of alpha-synuclein has significant implications in the development of PD, and understanding the mechanism may disclose potential therapeutic targets for PD and other related diseases.
Kim
Changyoun
C
Department of Biomedical Science and Technology, Konkuk University, Seoul, Korea.
Lee
Seung-Jae
SJ
D000818:Animals; D005089:Exocytosis / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport / Q000502:physiology; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D051844:alpha-Synuclein