Pathophysiology of ion channels in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) stands as the most prevalent and severe form of motor neuron disease, affecting an estimated 2 in 100,000 individuals worldwide. It is characterized by the progressive loss of cortical, brainstem, and spinal motor neurons, ultimately resulting in muscle weakness and death. Although the etiology of ALS remains poorly understood in most cases, the remodelling of ion channels and alteration in neuronal excitability represent a hallmark of the disease, manifesting not only during the symptomatic period but also in the early pre-symptomatic stages. In this review, we delve into these alterations observed in ALS patients and preclinical disease models, and explore their consequences on neuronal activities. Furthermore, we discuss the potential of ion channels as therapeutic targets in the context of ALS.

Keywords: Amyotrophic lateral sclerosis; Ion channels; Motor neurons; Neurodegeneration; Neuronal excitability.

Fig. 1

Alteration of ion channels along the motor pathway in ALS rodent models and patients. Channels shown in red are downregulated, while channels shown in green are upregulated. CIC1, chloride channel; Kir4.1, inward rectifier potassium channel; K_v1.1/K_v1.2/K_v7.2, voltage-gated potassium channels, Na+/K+-ATPase, sodium/potassium ATPase; Na_v1.3/Na_v1.4/Na_v1.6, voltage-gated sodium channels; NCX3, sodium/calcium exchanger