Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is a fatal neurodegenerative disease that causes loss of balance and motor co-ordination, eventually leading to paralysis. It is caused by the autosomal dominant inheritance of a long CAG trinucleotide repeat sequence within the ATXN3 gene, encoding for an expanded polyglutamine (polyQ) repeat sequence within the ataxin-3 protein. Ataxin-3 containing an expanded polyQ repeat is known to be highly prone to intraneuronal aggregation, and previous studies have demonstrated that protein quality control pathways, such as autophagy, are impaired in MJD patients and animal models of the disease. In this study, we tested the therapeutic potential of spermidine on zebrafish and rodent models of MJD to determine its capacity to induce autophagy and improve functional output. Spermidine treatment of transgenic MJD zebrafish induced autophagy and resulted in increased distances swum by the MJD zebrafish. Interestingly, treatment of the CMVMJD135 mouse model of MJD with spermidine added to drinking water did not produce any improvement in motor behaviour assays, neurological testing or neuropathology. In fact, wild type mice treated with spermidine were found to have decreased rotarod performance when compared to control animals. Immunoblot analysis of protein lysates extracted from mouse cerebellar tissue found little differences between the groups, except for an increased level of phospho-ULK1 in spermidine treated animals, suggesting that autophagy was indeed induced. As we detected decreased motor performance in wild type mice following treatment with spermidine, we conducted follow up studies into the effects of spermidine treatment in zebrafish. Interestingly, we found that in addition to inducing autophagy, spermidine treatment also induced apoptosis, particularly in wild type zebrafish. These findings suggest that spermidine treatment may not be therapeutically beneficial for the treatment of MJD, and in fact warrants caution due to the potential negative side effects caused by induction of apoptosis.

中文翻译：

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亚精胺治疗：诱导自噬但也诱导细胞凋亡？

马查多-约瑟夫病 (MJD)，也称为 3 型脊髓小脑共济失调，是一种致命的神经退行性疾病，会导致平衡和运动协调性丧失，最终导致瘫痪。它是由 ATXN3 基因内长 CAG 三核苷酸重复序列的常染色体显性遗传引起的，该序列编码 ataxin-3 蛋白内扩展的多聚谷氨酰胺 (polyQ) 重复序列。已知含有扩展的 PolyQ 重复序列的 Ataxin-3 极易发生神经元内聚集，之前的研究表明，蛋白质质量控​​制途径（例如自噬）在 MJD 患者和该疾病的动物模型中受到损害。在这项研究中，我们测试了亚精胺对斑马鱼和啮齿动物 MJD 模型的治疗潜力，以确定其诱导自噬和改善功能输出的能力。转基因 MJD 斑马鱼的亚精胺处理诱导自噬并导致 MJD 斑马鱼游泳的距离增加。有趣的是，用饮用水中添加亚精胺治疗 MJD CMVMJD135 小鼠模型，在运动行为测定、神经学测试或神经病理学方面没有产生任何改善。事实上，与对照动物相比，用亚精胺治疗的野生型小鼠的转棒性能有所下降。对从小鼠小脑组织中提取的蛋白质裂解物进行免疫印迹分析发现，除了亚精胺处理的动物中磷酸化 ULK1 水平增加之外，各组之间几乎没有差异，这表明自噬确实被诱导。由于我们发现野生型小鼠在接受亚精胺治疗后运动能力下降，因此我们对亚精胺治疗对斑马鱼的影响进行了后续研究。有趣的是，我们发现除了诱导自噬之外，亚精胺处理还诱导细胞凋亡，特别是在野生型斑马鱼中。这些发现表明，亚精胺治疗可能对 MJD 的治疗没有治疗益处，而且事实上，由于诱导细胞凋亡引起的潜在负面副作用，需要谨慎对待。