Pink1 interacts with α-synuclein and abrogates α-synuclein-induced neurotoxicity by activating autophagy

Abstract

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, characterized by degeneration of dopaminergic neurons in the substantia nigra. α-synuclein (α-syn) and PTEN-induced putative kinase (PINK)1 are two critical proteins associated with the pathogenesis of PD. α-syn induces mitochondrial deficits and apoptosis, PINK1 was found to alleviate α-syn-induced toxicity, but the mechanistic details remain obscure. Here, we show that PINK1 interacts with α-syn mainly in the cytoplasm, where it initiates autophagy. This interaction was dependent on the kinase activity of PINK1 and was abolished by deletion of the kinase domain or a G309D point mutation, an inactivating mutation in the kinase domain. Interaction between PINK1 and α-syn stimulated the removal of excess α-syn, which prevented mitochondrial deficits and apoptosis. Our findings provide evidence for a novel mechanism underlying the protective effects of PINK1 against α-syn-induced neurodegeneration and highlight a novel therapeutic target for PD treatment.

In vitro models of synucleinopathies: informing on molecular mechanisms and protective strategies

“…Moreover, Pink‐1 expression protected against the mitochondrial localization of α‐Syn prevented the inhibition of mitochondrial complex I, promoted autophagic clearance and greatly reduced α‐Syn induced apoptosis (Liu et al . ). Although not linked to PD via mutation, the mitochondrial chaperone protein, tumor necrosis factor receptor‐associated protein‐1 has also been reported to mitigate mitochondrial fragmentation in a number of cellular models expressing A53T mutant α‐Syn (Butler et al .…”

Cellular and Molecular Basis of Neurodegeneration in Parkinson Disease

“…DJ-1 reduced the accumulation and aggregation of α-synuclein via chaperone-mediated autophagy in both SH-SY5Y cells and PD animal models ( Xu et al, 2017 ). Interaction between PINK-1 and α-synuclein in the cytoplasm, which is dependent on the kinase activity of PINK1 and is abolished by point mutation of G309D in its kinase domain, enhanced the degradation of toxic α-synuclein via activation of autophagy ( Liu et al, 2017 ). Endoplasmic reticulum stressors, including thapsigargin, tunicamycin, 2-mercaptoethanol and Brefeldin A, activate PERK and then recruit MKK4 to lysosomes, accompanied by the activation of p38 MAPK which directly phosphorylates the receptor LAMP2A at sites T211 and T213, and further triggers chaperone-mediated autophagy to provide a pro-survival mechanism ( Li et al, 2017 ).…”

Mitochondrial integrity in neurodegeneration

“…Pink1 has been found to interact with alpha‐synuclein itself in mitochondria and stimulate its clearance via mitophagy, reducing the toxicity caused by alpha‐synuclein. This effect was abolished with a mutated form of Pink1, the point mutation G309D, which prevented Pink1 from interacting with alpha‐synuclein and being cleared from the mitochondria …”

“…This effect was abolished with a mutated form of Pink1, the point mutation G309D, which prevented Pink1 from interacting with alpha-synuclein and being cleared from the mitochondria. 78…”