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.

Complex neuroprotective and neurotoxic effects of histone deacetylases

“…Leucine‐rich repeat kinase‐2, binds to HDAC3 and phosphorylates it at Ser424, which resulted in a stimulation of HDAC3 activity (Han et al . ). Mutations in the Leucine‐rich repeat kinase‐2 gene are the most common genetic cause of both familial and sporadic Parkinson’s disease (Mata et al .…”

“…Additionally, leucine‐rich repeat kinase‐2‐mediated toxicity following 6‐hydroxydopamine treatment increased HDAC3 phosphorylation and its nuclear localization (Han et al . ).…”

“…HDAC3 has also been linked to Parkinson's disease, a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra (Olanow and Tatton 1999). Leucine-rich repeat kinase-2, binds to HDAC3 and phosphorylates it at Ser424, which resulted in a stimulation of HDAC3 activity (Han et al 2017). Mutations in the Leucine-rich repeat kinase-2 gene are the most common genetic cause of both familial and sporadic Parkinson's disease (Mata et al 2006).…”

“…Mutations in the Leucine-rich repeat kinase-2 gene are the most common genetic cause of both familial and sporadic Parkinson's disease (Mata et al 2006). Additionally, leucine-rich repeat kinase-2-mediated toxicity following 6-hydroxydopamine treatment increased HDAC3 phosphorylation and its nuclear localization (Han et al 2017).…”

Imbalance of Lysine Acetylation Contributes to the Pathogenesis of Parkinson’s Disease

“…LRRK2 phosphorylates HDAC3 at S424 and stimulates its deacetylase activity through an interaction, subsequently promoting deacetylation of H4K5/H4K12 and leading to repression of gene transcription. LRRK2 also promotes the nuclear translocation of HDAC3 by phosphorylating karyopherin subunits α2 and α6 [ 49 ]. The phosphorylation and nuclear translocation of HDAC3 are further increased under 6-OHDA treatment, and LRRK2 ultimately promotes 6-OHDA-induced damage by positively modulating HDAC3 [ 49 ].…”