| Title: |
Physiological and pathological roles of LRRK2 in the nuclear envelope integrity |
| Authors: |
Shani, Vered; Safory, Hazem; Szargel, Raymonde; Wang, Ninghan; Cohen, Tsipora; Elghani, Fatimah Abd; Hamza, Haya; Savyon, Mor; Radzishevsky, Inna; Shaulov, Lihi; Rott, Ruth; Lim, Kah-Leong; Ross, Christopher A; Bandopadhyay, Rina; Zhang, Hui; Engelender, Simone |
| Contributors: |
Reta Lila Weston Institute; National Institute of Neurological Disorders and Stroke; Israel Academy of Sciences and Humanities; The Allen and Jewel Prince Center for Neurodegenerative Disorders of the Brain; Dears Foundation Research; Hopkins-Technion Collaboration; Technion Research |
| Source: |
Human Molecular Genetics ; volume 28, issue 23, page 3982-3996 ; ISSN 0964-6906 1460-2083 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2019 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1093/hmg/ddz245 |
| DOI: |
10.1093/hmg/ddz245/30223217/ddz245.pdf |
| Availability: |
https://doi.org/10.1093/hmg/ddz245; http://academic.oup.com/hmg/advance-article-pdf/doi/10.1093/hmg/ddz245/30223217/ddz245.pdf; http://academic.oup.com/hmg/article-pdf/28/23/3982/33465422/ddz245.pdf |
| Rights: |
https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model |
| Accession Number: |
edsbas.5BEC81CA |
| Database: |
BASE |