Acta Neuropathologica

, Volume 115, Issue 1, pp 55-69

First online:

Huntington disease models and human neuropathology: similarities and differences

  • Jean Paul G. VonsattelAffiliated withThe Department of Pathology in the College of Physicians and Surgeons, The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia UniversityThe New York Brain Bank/Taub Institute, Columbia University, Children’s Hospital Email author 

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Huntington disease (HD) occurs only in humans. Thus, its natural pathogenesis takes place exclusively within the human brains expressing the causative, mutated protein huntingtin (mhtt). The techniques applicable to postmortem human HD brains are inadequate for investigating the cellular pathogenesis. The creation of genetically engineered animals represents a critical moment in neuroscience. Monitoring the actions of either normal, or abnormal proteins at subcellular levels, and at different time points is now possible thanks to these models. They are the necessary substitutes to investigate the wild type (whtt), or mhtt. The postmortem neuropathologic phenotype of the human HD is well documented. Its pattern and spectrum are highly predictable. From this point of view, the existent models do not exhibit the phenotypic constellation of changes seen in the human HD brains. On one hand, this deficit reflects the limitations of the methods of evaluation used in a clinical setting. On the other hand, it highlights the limitations of the animals. The validity of the models probably should be measured by their capacity of reproducing the cellular dysfunctions of HD rather than the phenotype of the postmortem human brains. Although not perfect, these models are essential for modeling the human disease in cells, which is not feasible with postmortem human HD brains. Nonetheless, their relevance to the patient population remains to be determined. Ultimately needed are means preventing the disease to occur, the discovery of which probably depends on these models.


Huntington disease Transgenic mouse Knockin mouse Mice gene carriers of the HD mutation