The expanded HTT CAG repeat causing Huntington’s disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans-factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery.

中文翻译：

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亨廷顿病和脊髓小脑共济失调 1 型中枢神经系统和外周的 CAG 重复不稳定性模式。

导致亨廷顿舞蹈病 (HD)的扩展HTT CAG 重复表现出体细胞扩张，旨在通过引发最终要求脆弱细胞的病理过程来推动疾病发病率。为了深入了解人类的体细胞扩张，我们对来自 7 名成人发病和 1 名青少年发病的 HD 个体的约 50 个中枢神经系统 (CNS) 和外周死后组织中的 CAG 扩张进行了全面的定量分析。我们还评估了ATXN1具有神经学和病理学上不同的重复扩增障碍、脊髓小脑共济失调 1 型 (SCA1) 的个体大脑区域的 CAG 重复扩增。我们的研究结果揭示了所有 HD 个体中组织不稳定性的相似特征，尤其是在 SCA1 个体中也很明显。在所有组织中都观察到 CAG 扩张，但程度不同，多个皮质区域和新纹状体在中枢神经系统和外周肝脏中往往具有最大的不稳定性。这些模式表明由疾病基因座独立的反式因子贡献的 CAG 扩展的不同倾向，并证明扩展本身不足以引起细胞类型或疾病特异性病理。相反，病理学可能反映由细胞类型和疾病的不同重复长度触发的不同毒性过程。我们还发现个体的HTT CAG 长度依赖性扩张倾向反映在所有组织和脑脊液中。我们的数据表明，外周细胞可能是在生物标志物检测中测量 CAG 扩增的有用来源，以用于治疗工作，促使人们努力剖析大脑和外周可能不同的潜在扩增机制。