Physiological and pathological roles of LRRK2 in the nuclear envelope integrity
Autor: | Mor Savyon, Fatimah Abd Elghani, Ruth Rott, Kah-Leong Lim, Tsipora Cohen, Rina Bandopadhyay, Ninghan Wang, Raymonde Szargel, Simone Engelender, Vered Shani, Lihi Shaulov, Christopher A. Ross, Hazem Safory, Hui Zhang, Inna Radzishevsky, Haya Hamza |
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Rok vydání: | 2019 |
Předmět: |
Nuclear Envelope
Biology Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 03 medical and health sciences Mice 0302 clinical medicine Loss of Function Mutation Genetics medicine Animals Humans Kinase activity Nuclear protein Phosphorylation Molecular Biology Genetics (clinical) Cells Cultured 030304 developmental biology 0303 health sciences Dopaminergic Neurons Parkinson Disease General Medicine Lamin Type A LRRK2 Cell biology nervous system diseases Rats Cytosol Cell nucleus medicine.anatomical_structure HEK293 Cells Nuclear lamina General Article Tumor Suppressor p53-Binding Protein 1 Nucleus 030217 neurology & neurosurgery Lamin |
Zdroj: | Hum Mol Genet |
ISSN: | 1460-2083 |
Popis: | 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. |
Databáze: | OpenAIRE |
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