Lee Shinrye, Kwon Younghwi, Kim Seyeon, Jo Myungjin, Jeon Yu-Mi, Cheon Mookyung, Lee Seongsoo, Kim Sang Ryong, Kim Kiyoung, Kim Hyung-Jun
Dementia Research Group, Korea Brain Research Institute, Daegu, South Korea.
Department of Brain and Cognitive Sciences, DGIST, Daegu, South Korea.
Front Cell Dev Biol. 2020 Nov 17;8:581942. doi: 10.3389/fcell.2020.581942. eCollection 2020.
Transactive response DNA-binding protein 43 (TDP-43)-induced neurotoxicity is currently well recognized as a contributor to the pathology of amyotrophic lateral sclerosis (ALS), and the deposition of TDP-43 has been linked to other neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). Recent studies also suggest that TDP-43-induced neurotoxicity is associated with ubiquitin-proteasome system (UPS) impairment. Histone deacetylase 6 (HDAC6) is a well-known cytosolic deacetylase enzyme that suppresses the toxicity of UPS impairment. However, the role of HDAC6 in TDP-43-induced neurodegeneration is largely unknown. In this study, we found that HDAC6 overexpression decreased the levels of insoluble and cytosolic TDP-43 protein in TDP-43-overexpressing N2a cells. In addition, TDP-43 overexpression upregulated HDAC6 protein and mRNA levels, and knockdown of elevated the total protein level of TDP-43. We further found that HDAC6 modulates TDP-43-induced UPS impairment via the autophagy-lysosome pathway (ALP). We also showed that TDP-43 promoted a short lifespan in flies and that the accumulation of ubiquitin aggregates and climbing defects were significantly rescued by overexpression of HDAC6 in flies. Taken together, these findings suggest that HDAC6 overexpression can mitigate neuronal toxicity caused by TDP-43-induced UPS impairment, which may represent a novel therapeutic approach for ALS.
目前，转录反应DNA结合蛋白43（TDP - 43）诱导的神经毒性被公认为是肌萎缩侧索硬化症（ALS）病理过程的一个促成因素，并且TDP - 43的沉积与其他神经退行性疾病有关，如额颞叶痴呆（FTLD）和阿尔茨海默病（AD）。最近的研究还表明，TDP - 43诱导的神经毒性与泛素 - 蛋白酶体系统（UPS）功能障碍有关。组蛋白去乙酰化酶6（HDAC6）是一种著名的胞质去乙酰化酶，可抑制UPS功能障碍的毒性。然而，HDAC6在TDP - 43诱导的神经退行性变中的作用在很大程度上尚不清楚。在本研究中，我们发现HDAC6过表达降低了TDP - 43过表达的N2a细胞中不溶性和胞质TDP - 43蛋白的水平。此外，TDP - 43过表达上调了HDAC6蛋白和mRNA水平，而敲低则提高了TDP - 43的总蛋白水平。我们进一步发现，HDAC6通过自噬 - 溶酶体途径（ALP）调节TDP - 43诱导的UPS功能障碍。我们还表明，TDP - 43缩短了果蝇的寿命，而HDAC6在果蝇中的过表达显著挽救了泛素聚集体的积累和攀爬缺陷。综上所述，这些发现表明HDAC6过表达可以减轻TDP - 43诱导的UPS功能障碍所引起的神经元毒性，这可能代表了一种治疗ALS的新方法。
