Role of viral infections in potassium channel-related cerebellar ataxia

小脑性共济失调是一种进行性神经退行性疾病，严重影响患者的日常生活

Cerebellar ataxia is a progressive neurodegenerative disease with major impact on the daily life of affected people, their families, and, on the health care system. There is no cure for cerebellar ataxia regardless of its origin. There is no effective treatment to slow the progression of symptoms that frequently lead to premature death. Ion channels have been implicated in the etiology of several form of cerebellar ataxia. For example, specific mutations in KCNC3, the gene encoding the Kv3.3 channel, such as the G592R point mutation, have been identified as the underlying genetic cause of late-onset spinocerebellar ataxia. Despite of these developments, there is no understanding of why late-onset cerebellar ataxias emerge in some but not all subjects with genetic mutations. There is also great variability in when during the lifespan of the affected subjects the symptoms emerge. Based on our unexpected preliminary observations, we hypothesize that disease onset in genetically vulnerable subjects is determined by host-pathogen interactions with particular emphasis on viral infections. Specifically, we assert that the synergistic activation of an intracellular signaling pathway that is targeted by both the mutant potassium channel and by viral defense mechanisms, impairs cellular function and results in the death of Purkinje cells. Our hypothesis and preliminary data challenge contemporary views on the etiology of cerebellar ataxia with implications for novel therapeutic strategies. We will test our hypothesis using cellular- and animal models with state-of-the-art neurobiological, molecular biological and immunobiological approaches.