[Altered axonal ion channel function in amyotrophic lateral sclerosis]

Fasciculation is a characteristic feature of amyotrophic lateral sclerosis (ALS). The ectopic firing of motor units usually arises from the motor nerve terminals, and occasionally from the motor neurons, indicating a wide-spread abnormality in axonal excitability properties. ALS is a multi-factorial disease; some gene abnormalities and environmental factors lead to a cell death through a complex cascade, including oxidative stress, mitochondrial dysfunction, excitotoxicity, and impaired axonal transport. It is important to elucidate the pathophysiology of axonal excitability in ALS, because increased axonal excitability would enhance oxidative stress and excitotoxicity, and therefore contribute to motor neuronal death. So far, two kinds of axonal ion channel abnormalities have been found; (1) increased persistent sodium currents, and (2) reduced potassium currents, both increasing axonal excitability and responsible for generation of fasciculations. In excitability testing, findings in ALS are characterized prolonged strength-duration time constant, suggesting increased persistent sodium currents, and greater threshold changes in depolarizing threshold electrotonus and greater supernormality, suggestive of impaired potassium channels. In relation to disease stage, persistent sodium currents increase in the early phase of the disease, possibly associated with collateral sprouting, and then, potassium currents decline. These serial changes in axonal properties could provide new insights into the pathophysiology of ALS, and implications for future therapeutic options.