Kinase inhibition of G2019S-LRRK2 enhances autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions
| Autor: | Sabine Hilfiker, Mattia Volta, Giovanni Piccoli, Peter P. Pramstaller, Andrew A. Hicks, Giulia Frapporti, Francesca Pischedda, Anne Picard, Giulia Lamonaca, Julia Obergasteiger, Corrado Corti, Veerle Baekelandt, Evy Lobbestael, Alexandros A. Lavdas, Sara Pizzi |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Immunology Neuropathology lcsh:RC254-282 Article 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine Cellular neuroscience Lysosome Macroautophagy medicine lcsh:QH573-671 Alpha-synuclein lcsh:Cytology Kinase Autophagy Cell Biology lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens LRRK2 Cell biology nervous system diseases 030104 developmental biology medicine.anatomical_structure chemistry 030217 neurology & neurosurgery Intracellular |
| Zdroj: | Cell Death Discovery Cell Death Discovery, Vol 6, Iss 1, Pp 1-13 (2020) |
| Popis: | The Parkinson's disease (PD)-associated kinase Leucine-Rich Repeat Kinase 2 (LRRK2) is a crucial modulator of the autophagy-lysosome pathway, but unclarity exists on the precise mechanics of its role and the direction of this modulation. In particular, LRRK2 is involved in the degradation of pathological alpha-synuclein, with pathogenic mutations precipitating neuropathology in cellular and animal models of PD, and a significant proportion of LRRK2 patients presenting Lewy neuropathology. Defects in autophagic processing and lysosomal degradation of alpha-synuclein have been postulated to underlie its accumulation and onset of neuropathology. Thus, it is critical to obtain a comprehensive knowledge on LRRK2-associated pathology. Here, we investigated a G2019S-LRRK2 recombinant cell line exhibiting accumulation of endogenous, phosphorylated alpha-synuclein. We found that G2019S-LRRK2 leads to accumulation of LC3 and abnormalities in lysosome morphology and proteolytic activity in a kinase-dependent fashion, but independent from constitutively active Rab10. Notably, LRRK2 inhibition was ineffective upon upstream blockade of autophagosome-lysosome fusion events, highlighting this step as critical for alpha-synuclein clearance. ispartof: CELL DEATH DISCOVERY vol:6 issue:1 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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