Correia Joana Sofia, Duarte-Silva Sara, Salgado António José, Maciel Patrícia
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães, Portugal.
Neural Regen Res. 2023 Jun;18(6):1203-1212. doi: 10.4103/1673-5374.355981.
Spinocerebellar ataxias are heritable neurodegenerative diseases caused by a cytosine-adenine-guanine expansion, which encodes a long glutamine tract (polyglutamine) in the respective wild-type protein causing misfolding and protein aggregation. Clinical features of polyglutamine spinocerebellar ataxias include neuronal aggregation, mitochondrial dysfunction, decreased proteasomal activity, and autophagy impairment. Mutant polyglutamine protein aggregates accumulate within neurons and cause neural dysfunction and death in specific regions of the central nervous system. Spinocerebellar ataxias are mostly characterized by progressive ataxia, speech and swallowing problems, loss of coordination and gait deficits. Over the past decade, efforts have been made to ameliorate disease symptoms in patients, yet no cure is available. Previous studies have been proposing the use of stem cells as promising tools for central nervous system tissue regeneration. So far, pre-clinical trials have shown improvement in various models of neurodegenerative diseases following stem cell transplantation, including animal models of spinocerebellar ataxia types 1, 2, and 3. However, contrasting results can be found in the literature, depending on the animal model, cell type, and route of administration used. Nonetheless, clinical trials using cellular implants into degenerated brain regions have already been applied, with the expectation that these cells would be able to differentiate into the specific neuronal subtypes and re-populate these regions, reconstructing the affected neural network. Meanwhile, the question of how feasible it is to continue such treatments remains unanswered, with long-lasting effects being still unknown. To establish the value of these advanced therapeutic tools, it is important to predict the actions of the transplanted cells as well as to understand which cell type can induce the best outcomes for each disease. Further studies are needed to determine the best route of administration, without neglecting the possible risks of repetitive transplantation that these approaches so far appear to demand. Despite the challenges ahead of us, cell-transplantation therapies are reported to have transient but beneficial outcomes in spinocerebellar ataxias, which encourages efforts towards their improvement in the future.
脊髓小脑共济失调是由胞嘧啶 - 腺嘌呤 - 鸟嘌呤扩增引起的遗传性神经退行性疾病，该扩增在相应的野生型蛋白中编码长谷氨酰胺序列（多聚谷氨酰胺），导致错误折叠和蛋白质聚集。多聚谷氨酰胺脊髓小脑共济失调的临床特征包括神经元聚集、线粒体功能障碍、蛋白酶体活性降低和自噬受损。突变的多聚谷氨酰胺蛋白聚集体在神经元内积累，并在中枢神经系统的特定区域导致神经功能障碍和死亡。脊髓小脑共济失调的主要特征是进行性共济失调、言语和吞咽问题、协调能力丧失和步态缺陷。在过去十年中，人们努力改善患者的疾病症状，但尚无治愈方法。先前的研究一直提议使用干细胞作为中枢神经系统组织再生的有前景的工具。到目前为止，临床前试验表明，在干细胞移植后，各种神经退行性疾病模型（包括脊髓小脑共济失调1型、2型和3型的动物模型）都有改善。然而，根据所使用的动物模型、细胞类型和给药途径的不同，文献中可以发现相互矛盾的结果。尽管如此，已经开展了将细胞植入退化脑区的临床试验，期望这些细胞能够分化为特定的神经元亚型并重新填充这些区域，重建受影响的神经网络。与此同时，继续此类治疗的可行性问题仍然没有答案，其长期效果仍然未知。为了确定这些先进治疗工具的价值，预测移植细胞的作用以及了解哪种细胞类型能为每种疾病带来最佳结果非常重要。需要进一步研究以确定最佳给药途径，同时不能忽视这些方法目前似乎需要的重复移植可能带来的风险。尽管我们面临挑战，但据报道细胞移植疗法在脊髓小脑共济失调中具有短暂但有益的效果，这鼓励我们在未来努力改进这些疗法。
