Department of Neurology, Michigan Medicine, University of Michigan, A. Alfred Taubman Biomedical Sciences Research Building, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA.
School of Medicine, University of Minho, Campus de Gualtar, Life and Health Sciences Research Institute (ICVS), Braga, Portugal.
Mol Neurobiol. 2019 May;56(5):3690-3701. doi: 10.1007/s12035-018-1331-2. Epub 2018 Sep 4.
Machado-Joseph disease, also known as spinocerebellar ataxia type 3, is a fatal polyglutamine disease with no disease-modifying treatment. The selective serotonin reuptake inhibitor citalopram was shown in nematode and mouse models to be a compelling repurposing candidate for Machado-Joseph disease therapeutics. We sought to confirm the efficacy of citalopram to decrease ATXN3 aggregation in an unrelated mouse model of Machado-Joseph disease. Four-week-old YACMJD84.2 mice and non-transgenic littermates were given citalopram 8 mg/kg in drinking water or water for 10 weeks. At the end of treatment, brains were collected for biochemical and pathological analyses. Brains of citalopram-treated YACMJD84.2 mice showed an approximate 50% decrease in the percentage of cells containing ATXN3-positive inclusions in the substantia nigra and three examined brainstem nuclei compared to controls. No differences in ATXN3 inclusion load were observed in deep cerebellar nuclei of mice. Citalopram effect on ATXN3 aggregate burden was corroborated by immunoblotting analysis. While lysates from the brainstem and cervical spinal cord of citalopram-treated mice showed a decrease in all soluble forms of ATXN3 and a trend toward reduction of insoluble ATXN3, no differences in ATXN3 levels were found between cerebella of citalopram-treated and vehicle-treated mice. Citalopram treatment altered levels of select components of the cellular protein homeostatic machinery that may be expected to enhance the capacity to refold and/or degrade mutant ATXN3. The results here obtained in a second independent mouse model of Machado-Joseph disease further support citalopram as a potential drug to be repurposed for this fatal disorder.
马查多-约瑟夫病，又称脊髓小脑共济失调 3 型，是一种致命的多聚谷氨酰胺疾病，目前尚无治疗方法。选择性 5-羟色胺再摄取抑制剂西酞普兰在线虫和小鼠模型中被证明是治疗马查多-约瑟夫病的一种有吸引力的再利用候选药物。我们试图在另一种马查多-约瑟夫病的小鼠模型中确认西酞普兰降低 ATXN3 聚集的疗效。将 4 周大的 YACMJD84.2 小鼠和非转基因同窝仔鼠给予西酞普兰 8mg/kg 饮用水或水 10 周。治疗结束时，收集大脑进行生化和病理分析。与对照组相比，西酞普兰治疗的 YACMJD84.2 小鼠的黑质和三个被检查的脑干核中含有 ATXN3 阳性包涵体的细胞百分比约减少了 50%。在小鼠的深部小脑核中未观察到 ATXN3 包涵体负荷的差异。免疫印迹分析证实了西酞普兰对 ATXN3 聚集物负担的影响。虽然西酞普兰治疗小鼠的脑干和颈脊髓的裂解物显示所有可溶性 ATXN3 形式减少，并且不溶性 ATXN3 有减少的趋势，但西酞普兰治疗和载体治疗的小鼠的小脑之间未发现 ATXN3 水平的差异。西酞普兰治疗改变了细胞蛋白稳态机制的某些成分的水平，这可能增强了重折叠和/或降解突变 ATXN3 的能力。在另一种马查多-约瑟夫病的独立小鼠模型中获得的结果进一步支持将西酞普兰作为一种潜在的药物重新用于这种致命疾病。
