Does loss of the normal protein function contribute to the pathogenesis of Huntington's disease?

Neurodegenerative disorders such as Huntington’s, Alzheimer’s, Parkinson’s and prion diseases are progressive and without a cure. A common finding is one of misfolded protein aggregates, conventionally believed to underlie pathogenesis via a toxic gain of function. Recently, a potential contribution of loss of normal protein function has come under the spotlight. With a focus on huntingtin, the protein involved in Huntington’s disease, this review examines the evidence for the conventional ‘gain of function’ model, before considering the hypothesis that a loss of function contributes to pathogenesis. In support of a primarily toxic gain of function are findings that huntingtin aggregates are neurotoxic in vitro. Additionally, aggregates of mutant huntingtin proteins have been detected prior to neuropathological changes, supporting a causal role. However, a dissociation between the neurons containing mutant huntingtin aggregates and those that are most vulnerable in Huntington’s disease indicates the possibility of a contribution from a loss of protein function. Evidence suggests a neuroprotective role for huntingtin; loss of its functions could feasibly lead to neurodegeneration. An exclusive role of loss of function is contradicted by the finding that genetic ablation of huntingtin protein does not cause Huntington’s disease, but a contribution from loss of function is supported by similarities between neuropathological and behavioural phenotypes in animal models of Huntington’s Disease and those produced by loss of the normal functions of huntingtin. Perhaps, therefore, both loss and gain of function are necessary processes in Huntington’s pathogenesis, with neither one sufficient to cause the disease alone. Review of the current evidence fails to elucidate an exact role for loss of function in Huntington’s disease pathogenesis. More information is required on the extent to which depletion of the normal protein causes, rather than accompanies, disease. In the meantime, attempts at drug discovery should be mindful of the possibility of a contribution from loss of function when designing treatments and interpreting trial results.