Ubiquitination increases parkin activity to promote autophagic a-synuclein clearance

Abstract

Parkinson's disease (PD) is a movement disorder associated with genetic and age related causes. Although autosomal recessive early onset PD linked to parkin mutations does not exhibit a-Synuclein accumulation, while autosomal dominant and sporadic PD manifest with a-Synuclein inclusions, loss of dopaminergic substantia nigra neurons is a commondenominator in PD. Here we show that decreased parkin ubiquitination and loss of parkin stability impair interaction with Beclin-1 and alter a-Synuclein degradation, leading to death of dopaminergic neurons. Tyrosine kinase inhibition increases parkin ubiquitination and interaction with Beclin-1, promoting autophagic a-Synuclein clearance and nigral neuron survival. However, loss of parkin via deletion increases a-Synuclein in the blood compared to the brain, suggesting that functional parkin prevents a-Synuclein release into the blood. These studies demonstrate that parkin ubiquitination affects its proteinstability and E3 ligase activity, possibly leading to a-Synuclein sequestration and subsequent clearance. © 2013 Lonskaya et al.