Physiological and pathological roles of LRRK2 in the nuclear envelope integrity

Vered Shani, Hazem Safory, Raymonde Szargel, Ninghan Wang, Tsipora Cohen, Fatimah Abd Elghani, Haya Hamza, Mor Savyon, Inna Radzishevsky, Lihi Shaulov, Ruth Rott, Kah Leong Lim, Christopher A. Ross, Rina Bandopadhyay, Hui Zhang, Simone Engelender

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3982-3996
Number of pages15
JournalHuman molecular genetics
Volume28
Issue number23
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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