Controversies and priorities in amyotrophic lateral sclerosis

Abstract

Two decades after the discovery that 20% of familial amyotrophic lateral sclerosis (ALS) cases were linked to mutations in the superoxide dismutase-1 (SOD1) gene, a substantial proportion of the remainder of cases of familial ALS have now been traced to an expansion of the intronic hexanucleotide repeat sequence in C9orf72. This breakthrough provides an opportunity to re-evaluate longstanding concepts regarding the cause and natural history of ALS, coming soon after the pathological unification of ALS with frontotemporal dementia through a shared pathological signature of cytoplasmic inclusions of the ubiquitinated protein TDP-43. However, with profound clinical, prognostic, neuropathological, and now genetic heterogeneity, the concept of ALS as one disease appears increasingly untenable. This background calls for the development of a more sophisticated taxonomy, and an appreciation of ALS as the breakdown of a wider network rather than a discrete vulnerable population of specialised motor neurons. Identification of C9orf72 repeat expansions in patients without a family history of ALS challenges the traditional division between familial and sporadic disease. By contrast, the 90% of apparently sporadic cases and incomplete penetrance of several genes linked to familial cases suggest that at least some forms of ALS arise from the interplay of multiple genes, poorly understood developmental, environmental, and age-related factors, as well as stochastic events.

Figure 1. Proposed mechanisms underlying neurodegeneration in ALS

Many of these pathways are mechanisms of cell death common to a range of neurological disorders, although in the case of amyotrophic lateral sclerosis (ALS), have been derived from studies undertaken predominantly using the SOD1 mouse model. Pathophysiological mechanisms involving more recent genetic discoveries, particularly the C9orf72 hexanucleotide repeat expansion, have yet to be elucidated. Neurodegeneration in ALS might reflect combinations of glutamate excitoxicity, generation of free radicals, mutant SOD1 enzymes, along with mitochondrial dysfunction and disruption of axonal transport processes through accumulation of neurofilament intracellular aggregates. Mutations in several ALS-related genes are associated with the formation of intracellular aggregates, which appear harmful to neurons. Activation of microglia results in secretion of proinflammatory cytokines resulting in further toxicity. Failure of cytoplasmic mitochondria induces increased susceptibility to glutamate-mediated excitotoxicity, perturbations in motor neuronal energy production, and apoptosis. Mitochondrial dysfunction is associated with increased production of reactive oxygen species (ROS). Cytoplasmic aggregates of SOD1 might directly inhibit conductance of VDAC1, thereby reducing the supply of ADP to mitochondria for ATP generation. Δψ=mitochondrial membrane potential.

Figure 2. The current macrogenetic landscape in ALS, highlighting the increasingly blurred boundary between familial and apparently sporadic disease

Only 5–10% of cases of amyotrophic lateral sclerosis (ALS) presenting to specialists report a positive family history of ALS or frontotemporal dementia (FTD). At least two-thirds of such cases can now be linked to one of four major genes, the largest group being those with expansions of the hexanucleotide repeat sequence in C9orf72. However, this expansion and mutations of the other genes identified are also detectable in a small but significant proportion of the 90–95% of cases of apparently sporadic ALS reporting no family history.

Figure 3. Hypothesised sequence of events in the pathogenesis of the ALS syndrome

The early substrate for amyotrophic lateral sclerosis (ALS; A) is likely to involve genetic, developmental, and environmental factors. For most apparently sporadic cases, multiple genetic factors with small individual effects might in part affect development and maturation of the nervous system. This process might result in a motor system architecture that is more permissive to pathological changes later in life, for example. Environmental triggers might then operate on an already primed system. Several molecular mechanisms for neurodegeneration have been postulated (B), common themes including excitotoxicity (or loss of inhibitory neuronal buffering) and oxidative stress. A common endpoint seems to be protein misaggregation, in which several recent genetic discoveries have implicated abnormal RNA biology. ALS is a syndrome with cases showing variable involvement of upper and lower motor neurons, and extramotor cognitive impairment (C), in which there can be significant variation in rates of progression. Although there are extremes of relatively isolated involvement of each of these compartments, termed primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), and frontotemporal dementia (FTD), all of these overlap with classic ALS on post-mortem neuropathological examination. A greater understanding of the nature of the apparent barriers between upper, lower, and extramotor neuronal populations might ultimate offer a disease-modifying strategy.