Advances in motor neurone disease

Abstract

Motor neurone disease (MND), the commonest clinical presentation of which is amyotrophic lateral sclerosis (ALS), is regarded as the most devastating of adult-onset neurodegenerative disorders. The last decade has seen major improvements in patient care, but also rapid scientific advances, so that rational therapies based on key pathogenic mechanisms now seem plausible. ALS is strikingly heterogeneous in both its presentation, with an average one-year delay from first symptoms to diagnosis, and subsequent rate of clinical progression. Although half of patients succumb within 3-4 years of symptom onset, typically through respiratory failure, a significant minority survives into a second decade. Although an apparently sporadic disorder for most patients, without clear environmental triggers, recent genetic studies have identified disease-causing mutations in genes in several seemingly disparate functional pathways, so that motor neuron degeneration may need to be understood as a common final pathway with a number of upstream causes. This apparent aetiological and clinical heterogeneity suggests that therapeutic studies should include detailed biomarker profiling, and consider genetic as well as clinical stratification. The most common mutation, accounting for 10% of all Western hemisphere ALS, is a hexanucleotide repeat expansion in C9orf72. This and several other genes implicate altered RNA processing and protein degradation pathways in the core of ALS pathogenesis. A major gap remains in understanding how such fundamental processes appear to function without obvious deficit in the decades prior to symptom emergence, and the study of pre-symptomatic gene carriers is an important new initiative.

Keywords: RNA; TDP-43; amyotrophic lateral sclerosis; anterior horn cell; autophagy; frontotemporal dementia; neurodegeneration; protein aggregation.

Figure 1.

Classification and nomenclature of MND. Note: MND can be classified according to clinical, neuropathological and genetic features. Importantly, a specific genetic or neuropathological category does not predict a completely distinct clinical phenotype. LMN, lower motor neurone; UMN, upper motor neurone; PLS, primary lateral sclerosis; PMA, progressive muscular atrophy.

Figure 2.

Pathogenic overview of ALS from the systems to tissue to neuronal to molecular level. (a) ALS affects motor neurons in the motor cortex (UMN) and anterior horn of the spinal cord (LMN) and corticospinal tract (CST). Bulbar dysfunction frequently arises as a combination of corticobulbar tract involvement and brainstem LMN loss. (b) The disease affects predominantly the anterior part of the brain, sparing regions such as the sensory cortex (inset: CD-68 stain of a section covering parts of the primary motor cortex ‘M’ and primary sensory cortex ‘S’). Spread of disease may occur along contiguous anatomical regions or along functional connections. Multifocal onset is a possibility (lower inset: TDP-43 stain of spinal motor neurons showing some neurons with normal nuclear TDP-43, and cells with pathological cytoplasmic inclusions). (c) Protein aggregation, predominantly of TDP-43, is observed in affected motor neurons. Spread of prion-like protein aggregates from cell to cell is hypothetical. Glutamate excitotoxicity, in part mediated by failure of synaptic uptake of glutamate by astrocytes, is another potential mechanism of cell to cell spread. Activated microglia with pro-inflammatory properties may play a role in disease progression. (d) TDP-43 is thought to leave the nucleus as part of a physiological stress response. Stress granules transiently stall translation of specific mRNAs, but release them again to translating polysomes after resolution of the stress. Due to its prion-like domain, TDP-43 in stress granules may be an initial step to pathological TDP-43 aggregates which are cleared by the ubiquitin-proteasome system and autophagy. Loss of nuclear TDP-43 may then lead to aberrant splicing of pre-mRNAs. Other RNA-binding proteins (RBP) may be trapped by ‘toxic’ RNA species, for example the hexanucleotide repeat expansion in C9orf72. This is also translated into aggregating dipeptide repeats that need to be cleared by the protein degradation machinery.