Prevention of intracellular degradation of I2020T mutant LRRK2 restores its protectivity against apoptosis

Biochemical and Biophysical Research Communications
Etsuro OhtaFumiya Obata

Abstract

Leucine-rich repeat kinase 2 (LRRK2) is the causal gene for autosomal dominant familial Parkinson's disease. We have previously reported a novel molecular feature characteristic to I2020T mutant LRRK2: higher susceptibility to post-translational degradation than the wild-type LRRK2. In the present study, we demonstrated that the protective effect of I2020T LRRK2 against hydrogen peroxide-induced apoptosis was impaired in comparison with the wild-type molecule. When the intracellular level of the protein had been allowed to recover by treatment with proteolysis inhibitors, the protective effect of I2020T LRRK2 against apoptosis was increased. We further confirmed that a decrease in the intracellular protein level of WT LRRK2 by knocking down resulted in a reduction of protectivity against apoptosis. These results suggest that higher susceptibility of I2020T mutant LRRK2 to intracellular degradation than the wild-type molecule may be one of the mechanisms involved in the neurodegeneration associated with this LRRK2 mutation.

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Citations

Jun 13, 2012·Proceedings of the National Academy of Sciences of the United States of America·Bernd K GilsbachArjan Kortholt
Jan 1, 2014·Molekuliarnaia biologiia·S N PchelinaT S Usenko
May 23, 2014·Frontiers in Molecular Neuroscience·Bernd K Gilsbach, Arjan Kortholt
Jun 18, 2016·BioMed Research International·Dong Hwan HoWongi Seol
Oct 11, 2016·Proteomics·Un-Beom Kang, Jarrod A Marto
May 6, 2015·The Biochemical Journal·Jing ZhaoR Jeremy Nichols

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