Mapping of the epitope of monoclonal antibody 2B4 to the proline-rich region of human Huntingtin, a region critical for aggregation and toxicity

Benjamin Dehay, Chantal Weber, Yvon Trottier, Anne Bertolotti
Biotechnol. J.. 2007-05-01; 2(5): 559-564
DOI: 10.1002/biot.200600249

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Huntington’s disease is a neurodegenerative disease caused by a polyglutamine
(polyQ) expansion in Huntingtin, which provokes aggregation of a proteolytic
amino-terminal fragment of the affected protein encompassing the polyQ expansion.
Accumulation of mutant Huntingtin somehow triggers cellular dysfunction and leads
to a progressive degeneration of striatal neurons. Despite considerable efforts,
the function of Huntingtin as well as the precise molecular mechanisms by which
the expanded polyQ elicits cellular dysfunction remain unclear. In addition, no
treatment is available to prevent, cure, or even slow down the progression of
this devastating disorder. Antibodies are valuable tools to understand protein
function and disease mechanisms. Here, we have identified the epitope recognized
by the mAb 2B4, a broadly used antibody generated against the amino-terminal
region of Huntingtin, which detects both aggregated and soluble Huntingtin. The
2B4 antibody specifically recognizes amino acids 50-64 of human Huntingtin but
not the murine homologous region. Furthermore, the 2B4 epitope resides within the
proline-rich region of Huntingtin, which is critical for polyQ aggregation and
toxicity. These properties suggest that the 2B4 antibody might be useful in
antibody-based therapeutic strategies.


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