RESUMEN
The sirtuins are members of the histone deacetylase family of proteins that participate in a variety of cellular functions and play a role in aging. We identified a potent inhibitor of sirtuin 2 (SIRT2) and found that inhibition of SIRT2 rescued alpha-synuclein toxicity and modified inclusion morphology in a cellular model of Parkinson's disease. Genetic inhibition of SIRT2 via small interfering RNA similarly rescued alpha-synuclein toxicity. Furthermore, the inhibitors protected against dopaminergic cell death both in vitro and in a Drosophila model of Parkinson's disease. The results suggest a link between neurodegeneration and aging.
Asunto(s)
Furanos/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Quinolinas/farmacología , Sirtuinas/antagonistas & inhibidores , Sirtuinas/metabolismo , alfa-Sinucleína/metabolismo , Acetilación , Animales , Animales Modificados Genéticamente , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Células Cultivadas , Modelos Animales de Enfermedad , Dopamina/fisiología , Relación Dosis-Respuesta a Droga , Drosophila melanogaster , Humanos , Modelos Moleculares , Neuronas/citología , Neuronas/efectos de los fármacos , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Conformación Proteica , ARN Interferente Pequeño/genética , Ratas , Sirtuina 1 , Sirtuina 2 , Sirtuinas/química , Sirtuinas/genética , Transfección , Tubulina (Proteína)/metabolismo , alfa-Sinucleína/genéticaRESUMEN
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.