Department of Human Genetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
Department of Research & Development, uniQure, Amsterdam, The Netherlands.
Mol Neurodegener. 2018 Jun 22;13(1):31. doi: 10.1186/s13024-018-0261-9.
Spinocerebellar ataxia type 3 (SCA3) is a progressive neurodegenerative disorder caused by expansion of the polyglutamine repeat in the ataxin-3 protein. Expression of mutant ataxin-3 is known to result in transcriptional dysregulation, which can contribute to the cellular toxicity and neurodegeneration. Since the exact causative mechanisms underlying this process have not been fully elucidated, gene expression analyses in brains of transgenic SCA3 mouse models may provide useful insights.
Here we characterised the MJD84.2 SCA3 mouse model expressing the mutant human ataxin-3 gene using a multi-omics approach on brain and blood. Gene expression changes in brainstem, cerebellum, striatum and cortex were used to study pathological changes in brain, while blood gene expression and metabolites/lipids levels were examined as potential biomarkers for disease.
Despite normal motor performance at 17.5 months of age, transcriptional changes in brain tissue of the SCA3 mice were observed. Most transcriptional changes occurred in brainstem and striatum, whilst cerebellum and cortex were only modestly affected. The most significantly altered genes in SCA3 mouse brain were Tmc3, Zfp488, Car2, and Chdh. Based on the transcriptional changes, α-adrenergic and CREB pathways were most consistently altered for combined analysis of the four brain regions. When examining individual brain regions, axon guidance and synaptic transmission pathways were most strongly altered in striatum, whilst brainstem presented with strongest alterations in the pi-3 k cascade and cholesterol biosynthesis pathways. Similar to other neurodegenerative diseases, reduced levels of tryptophan and increased levels of ceramides, di- and triglycerides were observed in SCA3 mouse blood.
The observed transcriptional changes in SCA3 mouse brain reveal parallels with previous reported neuropathology in patients, but also shows brain region specific effects as well as involvement of adrenergic signalling and CREB pathway changes in SCA3. Importantly, the transcriptional changes occur prior to onset of motor- and coordination deficits.
脊髓小脑共济失调 3 型（SCA3）是一种由 ataxin-3 蛋白中的多聚谷氨酰胺重复扩展引起的进行性神经退行性疾病。已知突变 ataxin-3 的表达会导致转录失调，这可能导致细胞毒性和神经退行性变。由于尚未完全阐明导致该过程的确切致病机制，因此对转基因 SCA3 小鼠模型的大脑进行基因表达分析可能会提供有用的见解。
在这里，我们使用多组学方法在大脑和血液中对表达突变人类 ataxin-3 基因的 MJD84.2 SCA3 小鼠模型进行了表征。研究了脑干部、小脑、纹状体和皮质的基因表达变化，以研究脑内的病理变化，同时检查了血液基因表达和代谢物/脂质水平，作为疾病的潜在生物标志物。
尽管在 17.5 个月龄时运动表现正常，但在 SCA3 小鼠的脑组织中观察到转录变化。大多数转录变化发生在脑干部和纹状体中，而小脑和皮质仅受到适度影响。SCA3 小鼠大脑中变化最显著的基因是 Tmc3、Zfp488、Car2 和 Chdh。基于转录变化，当对四个脑区的综合分析时，α-肾上腺素能和 CREB 途径最一致地改变。当检查单个脑区时，纹状体中最强烈地改变了轴突导向和突触传递途径，而脑干部则呈现最强的 pi-3 k 级联和胆固醇生物合成途径改变。与其他神经退行性疾病一样，在 SCA3 小鼠血液中观察到色氨酸水平降低和神经酰胺、二酰基和三酰基甘油水平升高。
SCA3 小鼠大脑中观察到的转录变化与先前报道的患者神经病理学相似，但也显示出脑区特异性效应以及 SCA3 中肾上腺素能信号和 CREB 途径变化的参与。重要的是，这些转录变化发生在运动和协调缺陷之前。
