ALS and other motor neuron disorders

Published June 2016 4 lectures
Prof. Kevin Talbot
University of Oxford, UK

Amyotrophic lateral sclerosis (ALS), the commonest form of motor neuron degeneration, remains one of the most feared diseases in medicine. It is currently incurable and there are few interventions which significantly impact on the relentlessly progressive course, which uniformly ends in death, usually from respiratory failure. In the last 20... read moreyears we have acquired a wealth of data about the genetic underpinnings of ALS. This has allowed disease modeling using in vitro and in vivo systems, illuminating a number of vulnerable pathways which represent plausible targets for drug therapy. We now know that ALS is a complex and heterogeneous clinical syndrome caused by a spectrum of age-dependent biological disturbances which converge on the corticomotorneuronal system. It is in essence a multiple-hit disease in which a genetic susceptibility profile interacts with a series of as yet undefined events which may be developmental, environmental or due to random biological events in aging. The inherent vulnerability of the motor system to degeneration, albeit manifesting as ALS in a small minority of individuals (1 in 400 lifetime risk), is likely to have explanations both at the level of the specific cells involved and also at the level of the oscillatory networks which have evolved rapidly in recent evolution.

The genes which are mutated in ALS can be grouped into three broad categories based on their known function: 1) RNA binding, processing and transportation (TDP-43, FUS, C9orf72 and others), 2) protein homeostasis (ubiquilin-2, optineurin, sequestome-1, VCP and others) and 3) axonal transport (profilin, dynactin, TUBA4A and others). These pathways are not mutually exclusive and how they interact is a major focus for ALS research.

A major departure for ALS research was the discovery of the dynamic hexanucleotide expansion in the gene of unknown function, C9orf72, as the commonest cause of both ALS and frontotemporal dementia (FTD). This gave a molecular basis unifying a series of clinical, genetic and pathological observations suggesting that ALS and FTD form a disease spectrum, united in most cases by alteration in the cellular homeostasis of TDP-43. While the mechanism of toxicity of the mutation is still unclear, it serves as a common target for therapy in approximately 10% of all cases.

ALS, one of a number of disorders of the motor neuron and its connections, is defined by combined degeneration of the upper (corticospinal) motor neuron and lower (spinomusuclar) motor neuron. There are also important disorders where the pathological process appears to be more selective for one end of the corticomotorneuronal axis. Spinal muscular atrophy (SMA) is an early onset disorder of pure lower motor neurons which has mixed developmental and degenerative components. Improved understanding of its pathogenesis first drew attention to the role of RNA binding proteins in motor neuron maintenance. It is now at an exciting stage of therapeutic development and may be one of the first disorders to be successfully treated with antisense oligonucleotide therapies. Kennedy’s disease is an under-recognised form of lower motor neuron degeneration which is X-linked and therefore only affects males. Its chronic course over decades raises challenges for therapy development. At the other end of the spectrum, the large number of genes in which mutation gives rise to pure corticospinal tract degeneration (hereditary spastic paraparesis) demonstrates that there are diverse pathways required to build and maintain the long motor neurons that control and facilitate movement by connecting executive voluntary centres and central pattern generators to the effector spinal motor neurons which serve as the quantal unit of motor action.