α-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity

Abstract

Alpha-synuclein is a neuronal protein implicated genetically in Parkinson's disease. alpha-synuclein localizes to the nucleus and presynaptic nerve terminals. Here we show that alpha-synuclein mediates neurotoxicity in the nucleus. Targeting of alpha-synuclein to the nucleus promotes toxicity, whereas cytoplasmic sequestration is protective in both cell culture and transgenic Drosophila. Toxicity of alpha-synuclein can be rescued by administration of histone deacetylase inhibitors in both cell culture and transgenic flies. Alpha-synuclein binds directly to histones, reduces the level of acetylated histone H3 in cultured cells and inhibits acetylation in histone acetyltransferase assays. Alpha-synuclein mutations that cause familial Parkinson's disease, A30P and A53T, exhibit increased nuclear targeting in cell culture. These findings implicate nuclear alpha-synuclein in promoting nigrostriatal degeneration in Parkinson's disease and encourage exploration of histone deacetylase inhibitors as potential therapies for the disorder.

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…More recently, the involvement of deficient epigenetic regulations has also been described, despite the fact that no particular HAT has been implicated in PD. Indeed, in Drosophila, toxic nuclear aggregates of α-synuclein interact with histone H3 and promote its deacetylation, possibly through a histone-"masking" mechanism [104]. Consistent with this result, several studies targeting HDAC members through sodium butyrate or valproic acid have shown an increase in histone acetylation, associated with prosurvival and anti-inflammatory effects, and decreased neurotoxicity markers [105][106][107][108][109][110].…”

Epigenetic Landscape of Parkinson's Disease: Emerging Role in Disease Mechanisms and Therapeutic Modalities

“…Consistent with these findings, the targeted downregulation of SIRT2 has been shown to rescue α-synuclein toxicity and dopaminergic cell loss in flies and in primary mesencephalic culture [31]. Moreover, toxicity associated with nuclear-targeted α-synuclein in both flies and SH-SY5Y cells can be rescued by employing HDAC inhibitors (HDACIs) [22,31,32]. In addition, oxidative stress is known to cause nuclear translocation of α-synuclein, which then binds to the promoter element (peroxisome proliferatorreceptor gamma coactivator-1) PGC1-αto to cause histone deacetylation and lowered PGC1-α levels [33].…”

“…However, studies performed in pharmacologically and genetically manipulated animal models and cell lines that indicate that SNCA expression can be altered by histone modifications. Indeed, in Drosophila models, nuclear-targeted α-synuclein has been shown to bind to histones and reduce histone H3 acetylation through its association with the HDAC SIRT2 [22]. Consistent with these findings, the targeted downregulation of SIRT2 has been shown to rescue α-synuclein toxicity and dopaminergic cell loss in flies and in primary mesencephalic culture [31].…”

“…Irrespective of the differences between missense mutations and gene multiplications, both variations of SNCA are known to cause the accumulation of the α-synuclein protein into cytoplasmic aggregates, which serve as the structural component of LBs and are signature pathological hallmarks of sporadic PD. The toxic effects of α-synuclein are also exerted in the neuronal nuclei, where it has been hypothesized that α-synuclein can perturb the distribution and organization of DNA and the epigenetic modifications of histone [22]. Although the role of DNA methylation and its link to PD pathogenesis is currently unclear, methylation of the SNCA gene may be involved in pathology via structural changes or the overexpression of the protein, leading to protein aggregation, or via impaired gene expression.…”

“…trapoxin); and the benzamides. One important study demonstrated that the neurotoxicity of α-synuclein in the nucleus could be rescued by the administration of HDAC inhibitors in both cellular models and transgenic fly models [22]. α-synuclein was found to bind directly to histones, reducing the levels of acetylated histone H3 in cultured cells and inhibiting acetylation in HAT assays [22].…”