Mutant huntingtin fragmentation in immune cells tracks Huntington’s disease progression
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
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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Brief Report Neuroscience

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 3

mHTT protein fragments are present in HD PBMCs.

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mHTT protein fragments are present in HD PBMCs. (A) HTT in PBMCs from 2 ...
(A) HTT in PBMCs from 2 subjects with HD and an age-matched control was immunoprecipitated with 2166, 2B7, or 4C9 anti-HTT antibodies, as compared with that precipitated by an IgG control. Immunoprecipitates were blotted with 4C9 and 2166 anti-HTT antibodies. Several HTT-specific bands were found in HD patient and control subject PBMC samples. (B) HTT protein in PBMCs from 2 patients with early-onset HD (HTT CAG repeat lengths of 76 and 59) and an age-matched control was immunoprecipitated with 2B7, 3B5H10, or 2166 anti-HTT antibodies. Immunoprecipitates were blotted with either the polyglutamine-specific MW1 antibody or the 2166 anti-HTT antibody. Several mHTT-specific bands were found in the lysates from the PBMCs from the patients with early-onset HD (colored boxes), including N-terminal HTT fragments (yellow boxes) immunoprecipitated with the 2B7 and 3B5H10 antibodies but not with the more C-terminal epitope-binding 2166. ID, immunodetection; IgG heavy chain, antibody heavy chain.