Mutant huntingtin fragmentation in immune cells tracks Huntington’s disease progression
Andreas Weiss, … , Ralph Andre, Sarah J. Tabrizi
Andreas Weiss, … , Ralph Andre, Sarah J. Tabrizi
Published September 17, 2012
Citation Information: J Clin Invest. 2012;122(10):3731-3736. https://doi.org/10.1172/JCI64565.
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Mutant huntingtin fragmentation in immune cells tracks Huntington’s disease progression

Abstract

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.

Authors

Andreas Weiss, Ulrike Träger, Edward J. Wild, Stephan Grueninger, Ruth Farmer, Christian Landles, Rachael I. Scahill, Nayana Lahiri, Salman Haider, Douglas Macdonald, Chris Frost, Gillian P. Bates, Graeme Bilbe, Rainer Kuhn, Ralph Andre, Sarah J. Tabrizi

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Figure 1

Relationship between HTT levels in peripheral immune cells and disease stage.

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Relationship between HTT levels in peripheral immune cells and disease s...
Total HTT and mHTT protein levels were quantified by TR-FRET in monocytes, T cells, and B cells. Total HTT quantification relies on simultaneous binding of 2B7 and 2166 anti-HTT antibodies. mHTT is quantified using the 2B7 antibody and a polyglutamine-specific antibody, MW1. (A) Total HTT levels in leukocytes showed no significant differences between patients with HD and control subjects or between HD gene carriers at different disease stages. (B) mHTT protein was detected in samples from patients with HD and pre-manifest HD mutation carriers, as compared with that in controls. Differences in mean mHTT levels in leukocytes were observed between pre-manifest and manifest HD patients (P < 0.01) and between pre-manifest and early-stage HD subjects (P = 0.051 and P < 0.05 for monocytes and T cells/B cells, respectively). Colored circles indicate multiple samples from a single subject. White circles indicate samples from individual subjects. Horizontal bars indicate the mean. Em, emission; Ex, excitation; N, N-terminal; C, C-terminal; Tb, terbium cryptate; polyQ, polyglutamine tract; pre-HD, pre-manifest HD sample; Early HD, early-stage HD sample; Moderate HD, moderate-stage HD sample.