Leucine-rich repeat kinase 2 exacerbates neuronal cytotoxicity through phosphorylation of histone deacetylase 3 and histone deacetylation

Kyung Ah Han, Woo Hyun Shin, Sungyeon Jung, Wongi Seol, Hyemyung Seo, CheMyong Ko, Kwang Chul Chung

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1-18
Number of pages18
JournalHuman molecular genetics
Volume26
Issue number1
DOIs
StatePublished - Jan 1 2017

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Leucine
Histones
Phosphotransferases
Phosphorylation
Oxidopamine
Histone Deacetylases
Parkinson Disease
Histone Code
MEF2 Transcription Factors
Karyopherins
histone deacetylase 3
Genetic Loci
Dopaminergic Neurons
Substantia Nigra
Epigenomics
Lysine
Chromatin
Cause of Death
Cell Death
Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Leucine-rich repeat kinase 2 exacerbates neuronal cytotoxicity through phosphorylation of histone deacetylase 3 and histone deacetylation. / Han, Kyung Ah; Shin, Woo Hyun; Jung, Sungyeon; Seol, Wongi; Seo, Hyemyung; Ko, CheMyong; Chung, Kwang Chul.

In: Human molecular genetics, Vol. 26, No. 1, 01.01.2017, p. 1-18.

Research output: Contribution to journalArticle

Han, Kyung Ah ; Shin, Woo Hyun ; Jung, Sungyeon ; Seol, Wongi ; Seo, Hyemyung ; Ko, CheMyong ; Chung, Kwang Chul. / Leucine-rich repeat kinase 2 exacerbates neuronal cytotoxicity through phosphorylation of histone deacetylase 3 and histone deacetylation. In: Human molecular genetics. 2017 ; Vol. 26, No. 1. pp. 1-18.
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