Post-translational modifications of soluble α-synuclein regulate the amplification of pathological α-synuclein.

Autor: Zhang S; Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA., Zhu R; Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA., Pan B; Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA., Xu H; The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Olufemi MF; The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Gathagan RJ; The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Li Y; Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.; Institute for Cognitive Neurodynamics, East China University of Science and Technology, Shanghai, China.; School of Mathematics, East China University of Science and Technology, Shanghai, China., Zhang L; Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA., Zhang J; Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA., Xiang W; Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA., Kagan EM; Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA., Cao X; Innovent Biologics, Inc., Suzhou, China., Yuan C; Alexion Pharmaceuticals, Inc., New Haven, CT, USA., Kim SJ; The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Williams CK; Section of Neuropathology, Department of Pathology and Laboratory Medicine, Ronald Reagan UCLA Medical Center and David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA., Magaki S; Section of Neuropathology, Department of Pathology and Laboratory Medicine, Ronald Reagan UCLA Medical Center and David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA., Vinters HV; Section of Neuropathology, Department of Pathology and Laboratory Medicine, Department of Neurology, and Brain Research Institute, Ronald Reagan UCLA Medical Center and David Geffen School of Medicine, University of California - Los Angeles, Los Angeles, CA, USA., Lashuel HA; Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Swiss Federal Institute of Technology, Lausanne, Switzerland., Garcia BA; Department of Biochemistry and Molecular Biophysics, Washington University St Louis, St Louis, MO, USA., James Petersson E; Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA., Trojanowski JQ; The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Lee VM; The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. vmylee@upenn.edu., Peng C; Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA. cpeng@mednet.ucla.edu.; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. cpeng@mednet.ucla.edu.; Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA. cpeng@mednet.ucla.edu.; Mary S. Easton Center for Alzheimer's Research, University of California, Los Angeles, Los Angeles, CA, USA. cpeng@mednet.ucla.edu.
Jazyk: angličtina
Zdroj: Nature neuroscience [Nat Neurosci] 2023 Feb; Vol. 26 (2), pp. 213-225. Date of Electronic Publication: 2023 Jan 23.
DOI: 10.1038/s41593-022-01239-7
Abstrakt: Cell-to-cell transmission and subsequent amplification of pathological proteins promote neurodegenerative disease progression. Most research on this has focused on pathological protein seeds, but how their normal counterparts, which are converted to pathological forms during transmission, regulate transmission is less understood. Here we show in cultured cells that phosphorylation of soluble, nonpathological α-synuclein (α-Syn) at previously identified sites dramatically affects the amplification of pathological α-Syn, which underlies Parkinson's disease and other α-synucleinopathies, in a conformation- and phosphorylation site-specific manner. We performed LC-MS/MS analyses on soluble α-Syn purified from Parkinson's disease and other α-synucleinopathies, identifying many new α-Syn post-translational modifications (PTMs). In addition to phosphorylation, acetylation of soluble α-Syn also modified pathological α-Syn transmission in a site- and conformation-specific manner. Moreover, phosphorylation of soluble α-Syn could modulate the seeding properties of pathological α-Syn. Our study represents the first systematic analysis how of soluble α-Syn PTMs affect the spreading and amplification of pathological α-Syn, which may affect disease progression.
(© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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