Ubiquitination Increases Parkin Activity to Promote Autophagic α-Synuclein Clearance |
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Authors: | Irina Lonskaya Nicole M Desforges Michaeline L Hebron Charbel E-H Moussa |
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Institution: | Department of Neuroscience, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, Washington, DC, United States of America.; National University of Singapore, Singapore, |
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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. |
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