In vivo evidence for reduced ion channel expression in motor axons of patients with amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is characterised by a progressive loss of motor units and the reinnervation of denervated muscle fibres by surviving motor axons. This reinnervation preserves muscle function until symptom onset, when some 60-80% of motor units have been lost. We have studied the changes in surviving motor neurons by comparing the nerve excitability properties of 31 single motor axons from patients with ALS with those from 21 single motor axons in control subjects. ALS motor axons were classified as coming from moderately or severely affected muscles according to the compound muscle action potential amplitude of the parent muscle. Compared with control units, thresholds were increased, and there was reduced inward and outward rectification and greater superexcitability following a conditioning impulse. These abnormalities were greater in axons from severely affected muscles, and were correlated with loss of fine motor skills. A mathematical model indicated that 99.1% of the differences between the moderately affected ALS and control units could be explained by a reduction in the expression of all ion channels. For the severely affected units, modelling required, in addition, an increase in the current leak through and under the myelin sheath. This might be expected if the anchoring proteins responsible for the paranodal seal were reduced. We conclude that changes in axonal excitability identified in ALS patients are best explained by a failure in the supply of ion channel and other membrane proteins from the diseased motor neuron, a conclusion consistent with recent animal and in vitro human data.

Conduction block in immune‐mediated neuropathy: paranodopathy versus axonopathy

“…Accordingly, a reduction in Na + and K + channel function may represent a process of a generalized reduction in channel density along enlarged axons with an increased load. A similar pattern of excitability change has been reported in single unit studies undertaken in patients with motor neuron disease, attributed to reduced channel densities along an enlarged axon supplying an abnormally large load of muscle fibres and impaired axonal transport of membrane proteins and channels resulting from the disease process .…”

The metastability of the proteome of spinal motor neurons underlies their selective vulnerability in ALS

“…Altered excitability has been observed in ALS patients (30,31), and in animal and cell models (reviewed in (32)), and recent work suggests that this altered excitability is consistent with a widespread decrease in the number of Na + and K + ion channels (33). Given that dysfunction occurs in a distal to proximal fashion (34), we hypothesised that axonal ion channels might be at particular risk of aggregation in ALS.…”

“…Of particular interest is the fact that altered axon excitability has been observed in ALS patients (30,31), and recent data predicts that this altered excitability is associated with a decrease in both Na + and K + channels (33). Supporting the notion that axons are particularly vulnerable is the fact that the distance from the cell body is an important factor in this context, as dysfunction occurs in a distal to proximal fashion (34).…”

Exciting Complexity: The Role of Motor Circuit Elements in ALS Pathophysiology

“…Increased axonal excitability in ALS is likely due to enhanced persistent axonal Na + conductance and impairments in axonal K + conductance (Bostock et al, 1995;Horn et al, 1996;Mogyoros et al, 1998;Kanai et al, 2006;Nakata et al, 2006;Tamura et al, 2006;Kiernan, 2006, 2009; Box 3) and was suggested to contribute to fasciculation potentials typical of ALS (de Carvalho and Swash, 2013; Howells et al, 2018; Figure 2 and Supplementary Table 2). However, others showed that fasciculations cannot be solely explained by increased Na + conductance, but must rely on impairments of all ion channels, including reduced inward and outward rectifying K + channels (Howells et al, 2018). Nevertheless, these studies can only provide indirect measures of overall neuronal excitability.…”