Journal Article

Subcellular Parkinson’s Disease-Specific Alpha-Synuclein Species Show Altered Behavior in Neurodegeneration

Abdullah, Rashed, Panick, Keith, Tzoulis, Charalampos, Patil, Ketan S., Chang, Emmanuel, Larsen, Jan Petter, Pal, Ramavati, Yang, Peter, Ho, Hsin-Pin, Rosen, Benjamin, Basak, Indranil, Neubert, Thomas A., Hoedt, Esthelle, Prabhudesai, Shubhangi, Lee, Sungsu, Alves, Guido, Møller, Simon G.

2017

Overview

Parkinson’s disease and other synucleinopathies are characterized by the presence of intra-neuronal protein aggregates enriched in the presynaptic protein α-synuclein. α-synuclein is considered an intrinsically disordered 14 kDa monomer, and although poorly understood, its transition to higher-order multimeric species may play central roles in healthy neurons and during Parkinson’s disease pathogenesis. In this study, we demonstrate that α-synuclein exists as defined, subcellular-specific species that change characteristics in response to oxidative stress in neuroblastoma cells and in response to Parkinson’s disease pathogenesis in human cerebellum and frontal cortex. We further show that the phosphorylation patterns of different α-synuclein species are subcellular specific and dependent on the oxidative environment. Using high-performance liquid chromatography and mass spectrometry, we identify a Parkinson’s disease enriched, cytosolic ~36-kDa α-synuclein species which can be recapitulated in Parkinson’s disease model neuroblastoma cells. The characterization of subcellular-specific α-synuclein features in neurodegeneration will allow for the identification of neurotoxic α-synuclein species, which represent prime targets to reduce α-synuclein pathogenicity.

• Publisher: Springer US,Springer Nature B.V
• Subject: Behavior / Biomedical and Life Sciences / Biomedicine / Brain - metabolism / Cell Biology / Cell Line, Tumor / Cell Membrane - chemistry / Cell Membrane - metabolism / Cell Nucleus - chemistry / Cell Nucleus - metabolism / Cerebellum / Chromatography, High Pressure Liquid - methods / Cortex (frontal) / Cytosol - chemistry / Cytosol - metabolism / High-performance liquid chromatography / Humans / Mass spectroscopy / Nerve Degeneration - metabolism / Neurobiology / Neuroblastoma / Neuroblasts / Neurodegeneration / Neurology / Neurosciences / Neurotoxicity / Oxidative stress / Parkinson Disease - metabolism / Parkinson's disease / Pathogenesis / Pathogenicity / Phosphorylation / Species / Subcellular Fractions - chemistry / Subcellular Fractions - metabolism / Synuclein