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.

Kinase inhibition of G2019S-LRRK2 enhances autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions / Obergasteiger, J.; Frapporti, G.; Lamonaca, G.; Pizzi, S.; Picard, A.; Lavdas, A. A.; Pischedda, F.; Piccoli, G.; Hilfiker, S.; Lobbestael, E.; Baekelandt, V.; Hicks, A. A.; Corti, C.; Pramstaller, P. P.; Volta, M.. - In: CELL DEATH DISCOVERY. - ISSN 2058-7716. - 6:1(2020), p. 45. [10.1038/s41420-020-0279-y]

Kinase inhibition of G2019S-LRRK2 enhances autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions

Frapporti G.;Lamonaca G.;Pizzi S.;Pischedda F.;Piccoli G.;
2020

Abstract

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.
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Obergasteiger, J.; Frapporti, G.; Lamonaca, G.; Pizzi, S.; Picard, A.; Lavdas, A. A.; Pischedda, F.; Piccoli, G.; Hilfiker, S.; Lobbestael, E.; Baekelandt, V.; Hicks, A. A.; Corti, C.; Pramstaller, P. P.; Volta, M.
Kinase inhibition of G2019S-LRRK2 enhances autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions / Obergasteiger, J.; Frapporti, G.; Lamonaca, G.; Pizzi, S.; Picard, A.; Lavdas, A. A.; Pischedda, F.; Piccoli, G.; Hilfiker, S.; Lobbestael, E.; Baekelandt, V.; Hicks, A. A.; Corti, C.; Pramstaller, P. P.; Volta, M.. - In: CELL DEATH DISCOVERY. - ISSN 2058-7716. - 6:1(2020), p. 45. [10.1038/s41420-020-0279-y]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11572/272610
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