PDF(Pubmed)
Abstract：
Intensive scientific research devoted in the recent years to understand the molecular mechanisms or neurodegeneration in spinocerebellar ataxias (SCAs) are identifying new pathways and targets providing new insights and a better understanding of the molecular pathogenesis in these diseases. In this consensus manuscript, the authors discuss their current views on the identified molecular processes causing or modulating the neurodegenerative phenotype in spinocerebellar ataxias with the common opinion of translating the new knowledge acquired into candidate targets for therapy. The following topics are discussed: transcription dysregulation, protein aggregation, autophagy, ion channels, the role of mitochondria, RNA toxicity, modulators of neurodegeneration and current therapeutic approaches. Overall point of consensus includes the common vision of neurodegeneration in SCAs as a multifactorial, progressive and reversible process, at least in early stages. Specific points of consensus include the role of the dysregulation of protein folding, transcription, bioenergetics, calcium handling and eventual cell death with apoptotic features of neurons during SCA disease progression. Unresolved questions include how the dysregulation of these pathways triggers the onset of symptoms and mediates disease progression since this understanding may allow effective treatments of SCAs within the window of reversibility to prevent early neuronal damage. Common opinions also include the need for clinical detection of early neuronal dysfunction, for more basic research to decipher the early neurodegenerative process in SCAs in order to give rise to new concepts for treatment strategies and for the translation of the results to preclinical studies and, thereafter, in clinical practice.
摘要：
近年来致力于了解脊髓小脑共济失调（SCA）的分子机制或神经变性的深入研究正在确定新的途径和靶标，从而提供了新的见解，并更好地了解了这些疾病的分子发病机理。在这份共识手稿中，作者讨论了他们目前对确定的导致或调节脊髓小脑共济失调神经退行性表型的分子过程的看法，以及将获得的新知识转化为治疗候选靶点的共同观点。讨论了以下主题：转录失调，蛋白质聚集，自噬,离子通道,线粒体的作用，RNA毒性，神经变性的调节剂和当前的治疗方法。共识的总体观点包括SCA中神经变性的共同愿景，作为多因素，渐进和可逆过程，至少在早期阶段。共识的具体观点包括蛋白质折叠失调的作用，转录,生物能学，在SCA疾病进展期间，钙处理和最终的细胞死亡以及神经元的凋亡特征。尚未解决的问题包括这些途径的失调如何触发症状的发作并介导疾病进展，因为这种理解可能允许在可逆性窗口内有效治疗SCA，以防止早期神经元损伤。常见的意见还包括需要临床检测早期神经元功能障碍，更多的基础研究来破译SCA中的早期神经退行性过程，以产生新的概念，用于治疗策略和将结果转化为临床前研究，此后,在临床实践中。
