title: Leucine-rich repeat kinase 2 exacerbates neuronal cytotoxicity through phosphorylation of histone deacetylase 3 and histone deacetylation.
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.
authors: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors: Kyung Ah
authors: KA
authors: Han
authors: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors: Woo Hyun
authors: WH
authors: Shin
authors: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors: Sungyeon
authors: S
authors: Jung
authors: InAm Neuroscience Research Center, Sanbon Medical Center, College of Medicine, Wonkwang University, Gunpo-si, Gyeonggi-do, Republic of Korea.
authors: Wongi
authors: W
authors: Seol
authors: Department of Molecular and Life Sciences, College of Science and Technology, Hanyang University, Ansan-si, Gyeonggi-do, Republic of Korea.
authors: Hyemyung
authors: H
authors: Seo
authors: Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors: CheMyong
authors: C
authors: Ko
authors: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors: Kwang Chul
authors: KC
authors: Chung
mesh_terms: D000107:Acetylation; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002470:Cell Survival; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology*; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016501:Neurites / Q000378:metabolism / Q000473:pathology*; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D051381:Rats; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D006657:Histones; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D000099186:Histone Deacetylase 3; C495280:LRRK2 protein, human