Leucine-rich repeat kinase 2 exacerbates neuronal cytotoxicity through phosphorylation of histone deacetylase3 and histone deacetylation.
- Title
- Leucine-rich repeat kinase 2 exacerbates neuronal cytotoxicity through phosphorylation of histone deacetylase3 and histone deacetylation.
- Author
- 서혜명
- Keywords
- DISEASE-ASSOCIATED MUTATIONS; MYOCYTE ENHANCER FACTOR-2; PARKINSONS-DISEASE; LRRK2 PHOSPHORYLATES; DOPAMINERGIC NEURON; PROTEIN; EXPRESSION; TOXICITY; HDAC3; DEATH
- Issue Date
- 2017-01
- Publisher
- OXFORD UNIV PRESS
- Citation
- HUMAN MOLECULAR GENETICS, v. 26, No. 1, Page. 1-18
- Abstract
- Parkinson's disease (PD) is characterized by slow, progressive degeneration of dopaminergic neurons in the substantia nigra. The cause of neuronal death in PD is largely unknown, but several genetic loci, including leucine-rich repeat kinase 2 (LRRK2), have been identified. LRRK2 has guanosine triphosphatase (GTPase) and kinase activities, and mutations in LRRK2 are the major cause of autosomal-dominant familial PD. Histone deacetylases (HDACs) remove acetyl groups from lysine residues on histone tails, promoting transcriptional repression via condensation of chromatin. Here, we demonstrate that LRRK2 binds to and directly phosphorylates HDAC3 at Ser-424, thereby stimulating HDAC activity. Specifically, LRRK2 promoted the deacetylation of Lys-5 and Lys-12 on histone H4, causing repression of gene transcription. Moreover, LRRK2 stimulated nuclear translocation of HDAC3 via the phoshorylation of karyopherin subunit α2 and α6. HDAC3 phosphorylation and its nuclear translocation were increased in response to 6-hydroxydopamine (6-OHDA) treatment. LRRK2 also inhibited myocyte-specific enhancer factor 2D activity, which is required for neuronal survival. LRRK2 ultimately promoted 6-OHDA-induced cell death via positive modulation of HDAC3. These findings suggest that LRRK2 affects epigenetic histone modification and neuronal survival by facilitating HDAC3 activity and regulating its localization.
- URI
- https://www.ncbi.nlm.nih.gov/pubmed/27798112https://repository.hanyang.ac.kr/handle/20.500.11754/71788
- ISSN
- 1460-2083; 0964-6906
- DOI
- 10.1093/hmg/ddw363
- Appears in Collections:
- COLLEGE OF SCIENCE AND CONVERGENCE TECHNOLOGY[E](과학기술융합대학) > MOLECULAR AND LIFE SCIENCE(분자생명과학과) > Articles
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