Physiological and pathological roles of LRRK2 in the nuclear envelope integrity.

Autor:	Shani V; Dept. of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel., Safory H; Dept. of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel., Szargel R; Dept. of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel., Wang N; Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA, USA., Cohen T; Dept. of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel., Elghani FA; Dept. of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel., Hamza H; Dept. of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel., Savyon M; Dept. of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel., Radzishevsky I; Dept. of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel., Shaulov L; Dept. of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel., Rott R; Dept. of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel., Lim KL; Department of Physiology, National University of Singapore, Singapore, Singapore., Ross CA; Department of Psychiatry, The Johns Hopkins Medical School, Baltimore, MD, USA., Bandopadhyay R; UK., Zhang H; Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA, USA., Engelender S; Dept. of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2019 Dec 01; Vol. 28 (23), pp. 3982-3996.
DOI:	10.1093/hmg/ddz245
Abstrakt:	Mutations in LRRK2 cause autosomal dominant and sporadic Parkinson's disease, but the mechanisms involved in LRRK2 toxicity in PD are yet to be fully understood. We found that LRRK2 translocates to the nucleus by binding to seven in absentia homolog (SIAH-1), and in the nucleus it directly interacts with lamin A/C, independent of its kinase activity. LRRK2 knockdown caused nuclear lamina abnormalities and nuclear disruption. LRRK2 disease mutations mostly abolish the interaction with lamin A/C and, similar to LRRK2 knockdown, cause disorganization of lamin A/C and leakage of nuclear proteins. Dopaminergic neurons of LRRK2 G2019S transgenic and LRRK2 -/- mice display decreased circularity of the nuclear lamina and leakage of the nuclear protein 53BP1 to the cytosol. Dopaminergic nigral and cortical neurons of both LRRK2 G2019S and idiopathic PD patients exhibit abnormalities of the nuclear lamina. Our data indicate that LRRK2 plays an essential role in maintaining nuclear envelope integrity. Disruption of this function by disease mutations suggests a novel phosphorylation-independent loss-of-function mechanism that may synergize with other neurotoxic effects caused by LRRK2 mutations. (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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