Unbiased Proteomics of Early Lewy Body Formation Model Implicates Active Microtubule Affinity-Regulating Kinases (MARKs) in Synucleinopathies

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Michael X HendersonVirginia M Y Lee

Abstract

Parkinson's disease (PD) patients progressively accumulate intracytoplasmic inclusions formed by misfolded α-synuclein known as Lewy bodies (LBs). LBs also contain other proteins that may or may not be relevant in the disease process. To identify proteins involved early in LB formation, we performed proteomic analysis of insoluble proteins in a primary neuron culture model of α-synuclein pathology. We identified proteins previously found in authentic LBs in PD as well as several novel proteins, including the microtubule affinity-regulating kinase 1 (MARK1), one of the most enriched proteins in this model of LB formation. Activated MARK proteins (MARKs) accumulated in LB-like inclusions in this cell-based model as well as in a mouse model of LB disease and in LBs of postmortem synucleinopathy brains. Inhibition of MARKs dramatically exacerbated α-synuclein pathology. These findings implicate MARKs early in synucleinopathy pathogenesis and as potential therapeutic drug targets.SIGNIFICANCE STATEMENT Neurodegenerative diseases are diagnosed definitively only in postmortem brains by the presence of key misfolded and aggregated disease proteins, but cellular processes leading to accumulation of these proteins have not been well eluc...Continue Reading

Citations

Sep 15, 2018·Neuropathology : Official Journal of the Japanese Society of Neuropathology·Chang ShenToru Iwaki
Sep 5, 2019·Acta Neuropathologica Communications·Lisa MaPaul J Hagerman
Sep 12, 2019·Translational Neurodegeneration·Naomi P VisanjiGabor G Kovacs
Apr 26, 2019·Journal of Neurochemistry·Yan Li, Mark R Cookson
Feb 23, 2020·Proceedings of the National Academy of Sciences of the United States of America·Anne-Laure Mahul-MellierHilal A Lashuel
Jun 2, 2018·Acta Neuropathologica Communications·Michael X HendersonVirginia M Y Lee
Mar 9, 2021·Journal of Alzheimer's Disease : JAD·Keith W VanDusenUNKNOWN MADCO-PC Investigators
Sep 25, 2021·Communications Biology·André D G LeitãoEmma Sierecki

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