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

Abstract

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.

Spinocerebellar ataxias: phenotypic spectrum of polyQ versus non-repeat expansion forms

“…Congenital forms and paroxystic episodes (seizures, hemiplegic migraine, ataxia, dystonia) were exclusively seen with non-repeat expansions, as in previous descriptions [11,19,34]. The increased occurrence of paroxystic episodes in non-expansion SCA was probably explained by the high frequency of genes (e.g., CACNA1A, KCNA2, ATP1A3) coding for ion channels [39][40][41]. Pathogenic variants in CACNA1A, KCNA2 and KMT2B were associated with epilepsy; seizures are a known feature of the rst two [42,43].…”

What Is the Role of the Dentate Nucleus in Normal and Abnormal Cerebellar Function?

“…The DN may contribute to the pathophysiology of neurologic disorders, either by direct involvement of the disease process, 25,86,87 as a consequence of abnormal Purkinje cell activity due to channelopathies or degeneration, 88,89 or both. The mechanisms underlying the manifestations of cerebellar ataxia have been extensively reviewed 4,5 and will not be discussed here.…”