Mechanisms Underlying ALS

Although the specific mechanisms underlying the development of ALS are currently unknown it is likely to involve a complex interplay of genetic factors and cellular processes. Some potential mechanisms include glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, impaired proteostasis, aberrant RNA metabolism, and neuroinflammation [3]. These mechanisms contribute to the progressive degeneration of motor neurones and the resulting muscle weakness observed in ALS.

• Glutamate excitotoxicity: Increased glutamate release from the presynaptic terminal and/or disruption of glutamate transporters which leads to high levels of glutamate at the synapse[4]. These high synaptic glutamate levels cause excitotoxicity or the overstimulation of glutamate transporters and ultimately neuronal cell death [4]. Riluzole, an FDA-approved drug for ALS, modulates glutamate excitotoxicity, highlighting the importance of this mechanism in ALS pathogenesis.

• Oxidative stress: Reactive oxygen species (ROS) accumulate as a result of an imbalance in the free radical formation and antioxidant defence which contributes to neuronal damage and death [3]. Mutations in the superoxide dismutase 1 (SOD1) gene, which encodes a key antioxidant enzyme, are a common cause of familial ALS [5].

• Mitochondrial dysfunction:  Alterations in mitochondrial morphology and dynamics (fusion/fission) are well described in ALS and can impact normal mitochondrial function [6]. Mitochondria dysfunction can contribute to increased ROS production, reduced ATP production, and disrupt calcium homeostasis all of which can impact neuronal survival [6].

• Impaired proteostasis: Mechanisms regulating proteostasis the process which controls the production, folding, translocation and degradation of proteins to maintain protein homeostasis is impaired in ALS [3]. This causes misfolded and aggregated proteins to accumulate within neurons which contributes to neuronal damage [7].

• Aberrant RNA metabolism: RNA metabolism dysregulation is another feature of the pathogenesis of ALS including transcription defects, alternate splicing changes, miRNA biogenesis, stress granule generation and RNA nucleocytoplasmic translocation [8]. Mutations in genes encoding RNA binding proteins, such as TDP-43 and FUS, which are known to play a role in RNA processing have been linked with ALS [9].

• Neuroinflammation: Neuroinflammation which is characterised by astrocyte and microglia activation, infiltration of lymphocytes and macrophages, and overproduction of inflammatory cytokines has been linked to neurodegeneration and neuronal loss [10]. Altered levels of inflammatory cytokines can be detected in the CNS as well as in the cerebrospinal fluid and blood of those with ALS [11].

Of the potential mechanisms described above oxidative stress, and mitochondrial dysfunction are considered initiating mechanisms in the pathogenesis of ALS [3]. The remaining mechanisms are thought to occur later and play a role in disease progression.

Progression of ALS

During the early stages of ALS patients may experience subtle muscle weakness, twitching or stiffness in the arms and legs [12]. As the disease progresses, muscle weakness and atrophy become more pronounced and widespread causing problems with mobility, swallowing, speech, and breathing [12]. In the later stages of the disease, patients experience near-total paralysis and often require ventilatory support to assist with breathing [12].  By far the most common cause of death in ALS is respiratory failure due to respiratory infection [13].

The rate at which ALS progresses can vary significantly between individuals with some patients deteriorating quickly and others more slowly. Those factors known to influence the rate of ALS progression include age of onset, site of onset and genetic factors [14]. The average survival time for most patients following an ALS diagnosis is typically around two to five years [15]. However, ensuring patients are diagnosed early, receive prompt treatment and have access to specialist care facilities are all factors that can significantly improve patient survival [16].

Undoubtedly, more research is needed to better understand the biological mechanisms underlying the development and progression of ALS. These new insights can be used to guide future treatment strategies to improve the quality of life and survival of patients suffering from this life-altering and extremely challenging disease.