Bushart David D, Shakkottai Vikram G
Ohio State University College of Medicine, Columbus, OH, United States.
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, United States.
Front Syst Neurosci. 2022 Jun 9;16:908569. doi: 10.3389/fnsys.2022.908569. eCollection 2022.
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.
离子通道基因突变是多种人类神经疾病的基础。从历史上看，离子通道基因的人类突变，即所谓的通道病，已被确定会导致发作性疾病。然而，在过去十年中，离子通道基因的突变已被证明会导致人类进行性神经退行性和神经发育障碍，特别是那些在小脑中富集的离子通道。鉴于先前的啮齿动物离子通道敲除模型几乎从未出现神经退行性变，这一结果出乎意料。导致人类共济失调的通道病，即使是半合子不足，也会导致小脑萎缩和小脑浦肯野神经元丢失。因此，与人类神经元相比，功能丧失的离子通道的啮齿动物神经元似乎对神经退行性变具有更强的抵抗力。因此，在导致共济失调的通道病中，人类和啮齿动物小脑神经元的易感性必然存在根本差异。在这篇综述中，我们探讨了人类神经元的特性，这些特性可能导致它们易受离子通道功能丧失突变继发的小脑变性影响。我们提出了一个模型，该模型考虑了人类和其他哺乳动物中已知的神经元离子通道密度的异速生长缩放，这可能解释了人类小脑神经元在导致共济失调的通道病中易发生变性的原因。我们还推测了小脑神经元在脊髓小脑共济失调（SCA）小鼠模型中发生变性的易感性，最近离子通道转录失调与该疾病的发病机制有关。
