Breaking Down The Potential Molecular Mechanisms Underlying Parkinson Disease

This has implications for the development of the neurodegenerative disorder Parkinson disease (PD) because altered degradation of alpha-synuclein has been implicated as a key step in the development of the disorder.

In the study, posttranslational modification of alpha-synuclein by processes such as by phosphorylation and nitration was shown to impair degradation of this protein by a mechanism known as chaperone-mediated autophagy (CMA) in isolated lysosomes, cultured dopaminergic cell lines, and cultured mouse neurons. Of relevance to PD, in which most of the neurons lost are dopaminergic neurons of the substantia nigra, dopamine-modified alpha-synuclein was poorly degraded by CMA and blocked the degradation of other proteins by CMA.

The authors therefore suggested that dopamine-induced inhibition of alpha-synuclein degradation by CMA increases the vulnerability of dopaminergic neurons to cellular stressors, thereby explaining the selective loss of dopaminergic neurons in individuals with PD.

Journal article: Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. Journal of Clinical Investigation. January 2, 2008.