Neurodegenerative Disease Huntington’s Disease


sleep disturbances often leads to an atypical neuroleptic agent, such as olanzapine, being chosen.2


A larger number of preclinical therapeutic studies and some emerging clinical trials are ongoing for HD.3


Many of the clinical trials


are based on promising effects of therapies in animal models of the disease. The possibility to reduce or inactivate the expression of the mutant huntingtin gene with different gene silencing approaches has recently gained significant attention.88–90


Technical concerns


remain, as does the choice of which region to target given that not all cells are likely to be reached using this technique. Naturally the striatum, with its severe pathology in human HD, has been the first site of choice for intracranial delivery in animal models. To what extent silencing the mutant huntingtin gene in the hypothalamus and/or the neuroendocrine system will have beneficial effects remains to be tested.


Importantly, hypothalamic dysfunction is implicated in mood disorders, obesity and type 2 diabetes. Intense research and drug development for these conditions is ongoing, with the aim of targeting distinct pathways in the hypothalamus.91,92


The potential of there being


common molecular changes between HD and other diseases affecting the hypothalamus opens up exciting possibilities for individuals with HD to benefit from the progress made for these much more common disorders. Likewise, HD with its monogenetic nature may provide a useful system model for similar disorders. Therefore, pre-clinical and clinical studies in HD may possibly facilitate advances that will be beneficial for a larger group of individuals affected by related disorders with hypothalamic dysfunction.


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Huntington’s Disease – A Hypothalamic Disorder?


Huntington’s disease has traditionally been viewed as a movement disorder caused by selective striatal pathology. Today, HD is increasingly being recognised as a disorder at the crossroads of neurology, psychiatry, cognitive medicine and genetics. It has distinct but widespread pathology in both the brain and the periphery. It is now clear that one aspect of the disease constitutes hypothalamic dysfunction and pathology. Given the spectrum of non-motor symptoms and signs arising from disturbed functions that are normally, at least in part, regulated by the hypothalamus, it is tempting to speculate that hypothalamic dysfunction plays a role in causing them. Experiments using specific animal models are ongoing to better establish such structure-to-function relationships. Animal studies have been instrumental in getting clinicians to appreciate the non-motor signs in HD and to closer investigate hypothalamic and neuroendocrine changes.46


Translational research will continue to be


pivotal for determination of the full extent and clinical significance of hypothalamic and neuroendocrine changes in HD. n


Åsa Petersén is an Associate Professor in Neuroscience at Lund University in Sweden. She is funded by a senior research fellowship from the Swedish Research Council allowing her to combine her research time with a residency in psychiatry. She directs the Translational Neuroendocrine Research Unit focusing on the neurobiological mechanisms underlying the psychiatric and metabolic aspects of Huntington’s Disease (HD). Dr Petersén is a Member of the Scientific and Bioethics Advisory Committee of the European HD Network.


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Hill JW, Elmquist JK, Elias CF, Hypothalamic pathways


EUROPEAN NEUROLOGICAL REVIEW


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