Open AccessUbiquitination Increases Parkin Activity to Promote Autophagic α-Synuclein Clearance
Author(s) -
Irina Lonskaya,
Nicole M. Desforges,
Michaeline Hebron,
Charbel Moussa
Publication year - 2013
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0083914
Subject(s) - parkin , ubiquitin , ubiquitin ligase , alpha synuclein , substantia nigra , dopaminergic , parkinson's disease , autophagy , biology , pink1 , microbiology and biotechnology , dopamine , endocrinology , medicine , genetics , disease , gene , apoptosis
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 α-Synuclein accumulation, while autosomal dominant and sporadic PD manifest with α-Synuclein inclusions, loss of dopaminergic substantia nigra neurons is a common denominator in PD. Here we show that decreased parkin ubiquitination and loss of parkin stability impair interaction with Beclin-1 and alter α-Synuclein degradation, leading to death of dopaminergic neurons. Tyrosine kinase inhibition increases parkin ubiquitination and interaction with Beclin-1, promoting autophagic α-Synuclein clearance and nigral neuron survival. However, loss of parkin via deletion increases α-Synuclein in the blood compared to the brain, suggesting that functional parkin prevents α-Synuclein release into the blood. These studies demonstrate that parkin ubiquitination affects its protein stability and E3 ligase activity, possibly leading to α-Synuclein sequestration and subsequent clearance.