title: Ubiquitination increases parkin activity to promote autophagic α-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 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.
authors.affiliation: Department of Neuroscience, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Irina
authors.initials: I
authors.lastname: Lonskaya
authors.affiliation: Department of Neuroscience, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Desforges
authors.affiliation: Department of Neuroscience, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Michaeline L
authors.initials: ML
authors.lastname: Hebron
authors.affiliation: Department of Neuroscience, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Charbel E-H
authors.initials: CE
authors.lastname: Moussa
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D051844:alpha-Synuclein / Q000097:blood / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein