Vulnerability of Human Cerebellar Neurons to Degeneration in Ataxia-Causing Channelopathies.

Mutations in ion channel genes underlie a number of human neurological diseases. Historically, human mutations in ion channel genes, the so-called channelopathies, have been identified to cause episodic disorders. In the last decade, however, mutations in ion channel genes have been demonstrated to result in progressive neurodegenerative and neurodevelopmental disorders in humans, particularly with ion channels that are enriched in the cerebellum. This was unexpected given prior rodent ion channel knock-out models that almost never display neurodegeneration. Human ataxia-causing channelopathies that result in even haploinsufficiency can result in cerebellar atrophy and cerebellar Purkinje neuron loss. Rodent neurons with ion channel loss-of-function appear to, therefore, be significantly more resistant to neurodegeneration compared to human neurons. Fundamental differences in susceptibility of human and rodent cerebellar neurons in ataxia-causing channelopathies must therefore be present. In this review, we explore the properties of human neurons that may contribute to their vulnerability to cerebellar degeneration secondary to ion channel loss-of-function mutations. We present a model taking into account the known allometric scaling of neuronal ion channel density in humans and other mammals that may explain the preferential vulnerability of human cerebellar neurons to degeneration in ataxia-causing channelopathies. We also speculate on the vulnerability of cerebellar neurons to degeneration in mouse models of spinocerebellar ataxia (SCA) where ion channel transcript dysregulation has recently been implicated in disease pathogenesis.