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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.

SUBMITTER: Liu J

PROVIDER: S-EPMC5636973 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The role of chaperone-mediated autophagy in neurotoxicity induced by alpha-synuclein after methamphetamine exposure.

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Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/?-synuclein aggregation.

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Ndfip1 Prevents Rotenone-Induced Neurotoxicity and Upregulation of α-Synuclein in SH-SY5Y Cells.

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SCD Inhibition Protects from α-Synuclein-Induced Neurotoxicity But Is Toxic to Early Neuron Cultures.

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Identification of ciliary neurotrophic factor receptor alpha as a mediator of neurotoxicity induced by extracellular alpha-synuclein

Project description:MES cells were treated with vehicle or 250 nM extracellular alpha-synuclein and plasma membrane proteins were labeled with biotin, followed by affinity purification. The biotinylated enriched membranous proteins were incubated with an alpha-synuclein peptide array membrane, washed extensively with TBS-T, followed by incubation with avidin-HRP. The positive spots were excised and the bound proteins were eluted. The elutions from consecutive spots were combined before trypsin digestion and analysis of peptides by LC-MS/MS.

2009-12-01 | PRD000155 | Pride

α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies.

Project description:Aggregation of α-synuclein, the hallmark of α-synucleinopathies such as Parkinson's disease, occurs in various glycosphingolipidoses. Although α-synuclein aggregation correlates with deficiencies in the lysosomal degradation of glycosphingolipids (GSL), the mechanism(s) involved in this aggregation remains unclear. We previously described the aggregation of α-synuclein in Krabbe's disease (KD), a neurodegenerative glycosphingolipidosis caused by lysosomal deficiency of galactosyl-ceramidase (GALC) and the accumulation of the GSL psychosine. Here, we used a multi-pronged approach including genetic, biophysical and biochemical techniques to determine the pathogenic contribution, reversibility, and molecular mechanism of aggregation of α-synuclein in KD. While genetic knock-out of α-synuclein reduces, but does not completely prevent, neurological signs in a mouse model of KD, genetic correction of GALC deficiency completely prevents α-synuclein aggregation. We show that psychosine forms hydrophilic clusters and binds the C-terminus of α-synuclein through its amino group and sugar moiety, suggesting that psychosine promotes an open/aggregation-prone conformation of α-synuclein. Dopamine and carbidopa reverse the structural changes of psychosine by mediating a closed/aggregation-resistant conformation of α-synuclein. Our results underscore the therapeutic potential of lysosomal correction and small molecules to reduce neuronal burden in α-synucleinopathies, and provide a mechanistic understanding of α-synuclein aggregation in glycosphingolipidoses.

| S-EPMC6102231 | biostudies-literature

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