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

Grueninger, Stephan (2012) Mutant huntingtin fragmentation in immune cells tracks Huntington’s disease progression. Journal of Clinical Investigation.


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 (m)HTT levels are expected to proceed to human trials, but non-invasive 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 HD patient leukocytes. Mean mHTT levels in monocytes, T cells and B cells differed significantly between HD patients 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 HD patients. Mutant HTT N-terminal fragments detected in HD monocytes 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 non-invasive disease biomarker.

Item Type: Article
Date Deposited: 27 Apr 2016 23:45
Last Modified: 27 Apr 2016 23:45


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