Neurology Central

Could fingolimod be repurposed for Huntington’s disease?

Huntington’s disease (HD) is a hereditary neurodegenerative disorder characterized by a triad of motor, psychiatric and cognitive symptoms. It is usually manifested between 30–50 years of age, with an estimated prevalence of 10 per 100,000 inhabitants in Europe. HD is caused by a CAG repeat expansion in the huntingtin gene (HTT) that translates to a repeat of polyglutamines, resulting in the formation of aggregates of the mutant protein within the cell. Although huntingtin is expressed throughout the brain, the pathology is most prominent in the striatum, cortex and, as evidenced more recently, in the hippocampus [1, 2]. The gradual deterioration of the physical, intellectual, and emotional capacity of HD patients, whose life expectancy is 15–20 years following diagnosis, has an important social and economic impact in sufferers, people at risk and relatives. Unfortunately, current HD treatments only temporarily relieve motor impairment, but do not delay or halt the progression of the disease. Therefore, it is important to develop treatments aimed at alleviating or delaying the symptoms from its beginning, in order to improve patients’ quality of life.

For the past decade, efforts to find new treatments for HD have been focused on blocking neuronal death. However, compelling evidence demonstrates that cellular dysfunction precedes overt cell death by many years in humans and animal models [3, 4]. This suggests that early deficits in HD are likely caused by synaptic dysfunction, rather than as a consequence of neuronal death. Accordingly, cognitive impairment appears long before physical decline in HD patients and mice [5, 6]. In light of this evidence, we have focused our work on the identification of harmful mechanisms triggered by mutant huntingtin that affect neuronal plasticity from the early stages of the disease. The specific aim of this investigation was to search for drugs able to enhance synaptic plasticity and improve cognitive dysfunction in HD.

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