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.
Highlights
Parkinson’s disease (PD) is predominantly sporadic, but some disease-causing mutations suggest a genetic component in the pathogenesis of this disorder
Parkin interaction with Beclin-1 is decreased in sporadic PD brains
We previously demonstrated accumulation of insoluble parkin within autophagic vacuoles (AVs) in post-mortem sporadic PD brains [24], suggesting that decreased parkin solubility leads to autophagic defects
Summary
Parkinson’s disease (PD) is predominantly sporadic, but some disease-causing mutations suggest a genetic component in the pathogenesis of this disorder. Loss of parkin function (via mutations) is usually not associated with LBs [12], but some parkin-linked patients have LBs [13,14,15]. Parkin is inactivated in sporadic PD, and accumulation of amyloidogenic proteins alters parkin solubility and enzymatic activity [26,27,28], suggesting that loss of parkin function is due to changes in protein stability independent of disease-causing mutations. Insoluble parkin is associated with loss of tyrosine hydroxylase (TH+) neurons in sporadic PD [24]. Despite the lack of genetic link between parkin and a-Synuclein, the role of parkin is supported in both familial autosomal recessive and sporadic PD [29]
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