Neuroscience Discovery, Novartis Institutes for Biomedical Research, Basel, Switzerland.
J Clin Invest. 2012 Oct;122(10):3731-6. doi: 10.1172/JCI64565. Epub 2012 Sep 17.
Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder caused by an expanded CAG repeat in the gene encoding huntingtin (HTT). Therapeutic approaches to lower mutant HTT (mHTT) levels are expected to proceed to human trials, but noninvasive quantification of mHTT is not currently possible. The importance of the peripheral immune system in neurodegenerative disease is becoming increasingly recognized. Peripheral immune cells have been implicated in HD pathogenesis, but HTT levels in these cells have not been quantified before. A recently described time-resolved Förster resonance energy transfer (TR-FRET) immunoassay was used to quantify mutant and total HTT protein levels in leukocytes from patients with HD. Mean mHTT levels in monocytes, T cells, and B cells differed significantly between patients with HD and controls and between pre-manifest mutation carriers and those with clinical onset. Monocyte and T cell mHTT levels were significantly associated with disease burden scores and caudate atrophy rates in patients with HD. mHTT N-terminal fragments detected in HD PBMCs may explain the progressive increase in mHTT levels in these cells. These findings indicate that quantification of mHTT in peripheral immune cells by TR-FRET holds significant promise as a noninvasive disease biomarker.
亨廷顿病（HD）是一种致命的遗传性神经退行性疾病，由编码亨廷顿蛋白（HTT）的基因中 CAG 重复扩增引起。降低突变 HTT（mHTT）水平的治疗方法有望进入人体试验，但目前无法无创地定量 mHTT。外周免疫系统在神经退行性疾病中的重要性越来越受到重视。外周免疫细胞已被牵连到 HD 的发病机制中，但这些细胞中的 HTT 水平以前没有被量化过。最近描述的时间分辨荧光共振能量转移（TR-FRET）免疫测定法被用于量化来自 HD 患者的白细胞中的突变和总 HTT 蛋白水平。与对照组和有临床发病的无症状突变携带者相比，HD 患者单核细胞、T 细胞和 B 细胞中的 mHTT 水平差异显著。在 HD 患者中，单核细胞和 T 细胞 mHTT 水平与疾病负担评分和尾状核萎缩率显著相关。在 HD PBMC 中检测到的 mHTT N 端片段可能解释了这些细胞中 mHTT 水平的逐渐增加。这些发现表明，通过 TR-FRET 在外周免疫细胞中定量 mHTT 作为一种非侵入性疾病生物标志物具有很大的潜力。
