Controversies and priorities in amyotrophic lateral sclerosis

Abstract

Summary 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.

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…ALS is a fatal adult-onset neuromuscular disorder, affecting upper and lower motor neurons, and leading to progressive muscle wasting, paralysis, and, eventually, death [113]. Motor neuron degeneration is associated primarily with the pathological aggregation of ubiquitin, fused in sarcoma protein, and the transactive response DNA binding protein (TAR) DNAbinding protein of 43-kDa in the cytoplasm of motor neuron cell bodies [114,115].…”

“…These mutations confer an adverse pro-apoptotic activity to SOD1, which is associated with oxidative damage and mitochondrial function disturbance, leading to increased neuronal vulnerability. Most of the SOD1 mutant proteins are prone to aggregation, and cytoplasmic inclusions have been detected in human patients and model systems [113,117]. Even if the premature death of motor neurons is determinant in the onset of this disorder, the molecular mechanism of neuronal degeneration are multi-factorial, and the cause of ALS pathogenicity remains a matter of debate [118,119].…”

Disparity of outcomes: the limits of modeling amyotrophic lateral sclerosis in murine models and translating results clinically

“…Mounting evidence supports a heterogeneous cascade of events that underlie the inherent pathomechanism(s) of ALS (6). Clinically, patients present with a phenotypically heterogeneous disease that can affect site of onset, rate of disease progression, upper and/or lower motor neuron involvement, and whether the phenotype is strictly behavioural or elicits some form of cognitive impairment (75).…”

“…As discussed elsewhere, current evidence suggests that the disease presents along a continuum which ranges from "pure" ALS to frontotemporal dementia (6,101). Employing a heterogeneous study population in a clinical trial with undefined disease mechanisms will not see positive outcomes unless all disease pathways converge for the ultimate phenotypic expression.…”

“…Implicated in up to 20% of all fALS cases, more than 180 toxic-gain-of-function mutations in the SOD1 gene has been described throughout all exonic sequences (Figure 2; 3,5). The vast majority of ALS patients (95%), however, suffer from a sporadic form of the disease (sALS) in which unknown etiological factors are causal in inducing the disease (4,6).…”