Mutant huntingtin fragmentation in immune cells tracks Huntington%26apos;s disease progression

作者：Weiss Andreas; Traeger Ulrike; Wild Edward J; Grueninger Stephan; Farmer Ruth; Landles Christian; Scahil Rachael I; Lahiri Nayana; Haider Salman; Macdonald Douglas; Frost Chris; Bates Gillian P; Bilbe Graeme; Kuhn Rainer; Andre Ralph; Tabrizi Sarah J^*

来源：Journal of Clinical Investigation, 2012, 122(10): 3731-3736.

DOI：10.1172/JCI64565

Huntington%26apos;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 Forster 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.

• 出版日期2012-10