Normal huntingtin function: an alternative approach to Huntington's disease

  title={Normal huntingtin function: an alternative approach to Huntington's disease},
  author={Elena Cattaneo and Chiara Zuccato and Marzia Tartari},
  journal={Nature Reviews Neuroscience},
Several neurological diseases are characterized by the altered activity of one or a few ubiquitously expressed cell proteins, but it is not known how these normal proteins turn into harmful executors of selective neuronal cell death. We selected huntingtin in Huntington's disease to explore this question because the dominant inheritance pattern of the disease seems to exclude the possibility that the wild-type protein has a role in the natural history of this condition. However, even in this… 
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The pathogenic cascades described in the literature through which mutant huntingtin leads to neuronal demise are discussed, and it is suggested that due to the ubiquitous presence of huntingtin, astrocytes are also dysfunctional, and neuroinflammation may additionally contribute to Huntington's disease pathology.
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Review of the current evidence fails to elucidate an exact role for loss of function in Huntington’s disease pathogenesis, but suggests a neuroprotective role for huntingtin; loss of its functions could feasibly lead to neurodegeneration.
Therapeutic Strategies for Huntington's Disease.
This review focuses on the current state of therapeutic development for the treatment of HD, including the preclinical and clinical development of small molecules and molecular therapies.
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  • 2003
The results of a new study on the effects of the mutated huntingtin protein are discussed and it is suggested that the HD mutation damages cells by perturbing multiple parallel pathways by gain-of-function and possibly also dominant negative mechanisms.
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  • 2001
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Although traditionally considered a “gain-of-function” disease, the recent finding that normal huntingtin has an important role in neuronal survival suggests that loss of function of the normal protein might contribute to HD, also disclosing new perspectives on the therapeutical approach to the pathology.