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The changing scene of amyotrophic lateral sclerosis

Key Points

  • Amyotrophic lateral sclerosis (ALS) is a clinical, genetic and pathogenic heterogenous condition. It lies at one end of a spectrum of a single biological condition, with FTLD at the other end. Many patients present symptoms and signs of both conditions.

  • ALS can be a proteinopathy, a ribonucleopathy or a mixture of both. The prion-like behaviour of some mutant proteins may contribute to the cellular spread of disease and thus to the progressive nature of ALS.

  • Non-canonical protein functions may contribute to the mechanism of ALS or the vulnerability of motor neurons in this disease.

  • ALS and FTLD join the list of the repeat expansion diseases: a hexanucleotide repeat in a non-coding sequence of C9ORF72 (chromosome 9 open reading frame 72) is the most prevalent identified cause of ALS.

  • Emerging data highlight the contribution of glial cells to motor neuron degeneration. Impaired oligodendrocyte-mediated trophic support has been shown to contribute to motor neuron degeneration.

  • Disease modifiers are factors that do not cause disease on their own but modify the phenotypic expression of the disorder. They may be targets for therapeutic intervention, even if the cause of the disease remains unknown. Targeting disease modifiers is important, as the cause of the sporadic form of neurodegenerative disorders, which is seen in a large majority of patients, is not known.

Abstract

Several recent breakthroughs have provided notable insights into the pathogenesis of amyotrophic lateral sclerosis (ALS), with some even shifting our thinking about this neurodegenerative disease and raising the question as to whether this disorder is a proteinopathy, a ribonucleopathy or both. In addition, these breakthroughs have revealed mechanistic links between ALS and frontotemporal dementia, as well as between ALS and other neurodegenerative diseases, such as the cerebellar atrophies, myotonic dystrophy and inclusion body myositis. Here, we summarize the new findings in ALS research, discuss what they have taught us about this disease and examine issues that are still outstanding.

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Figure 1: Overview of events in the pathogenesis of amyotrophic lateral sclerosis.
Figure 2: Possible pathogenic mechanism of misfolded SOD1-induced toxicity.
Figure 3: Possible pathogenic mechanism of mutant TDP43.
Figure 4: Possible pathogenic mechanism of motor neuron degeneration induced by the C9ORF72 repeat expansion.

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Correspondence to Wim Robberecht.

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Supplementary information

Supplementary information S1

Schematic representation of the most important proteins with their molecular domains in which mutations cause ALS. (PDF 360 kb)

Supplementary information S2

Mutations in proteins involved in protein degradation cause ALS. (PDF 276 kb)

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Glossary

Frontotemporal dementia

This term refers to the clinical presentation of the behavioural variant of frontotemporal lobe degeneration.

Frontotemporal lobe degeneration

(FTLD). A pathology that is characterized by frontal and temporal lobe atrophy. It presents with behavioural or language abnormalities.

Unfolded protein response

(UPR). This denotes a stress reaction of the cell in response to the accumulation of misfolded proteins in the endoplasmic reticulum. It aims to stall protein translation and increase the production of chaperone molecules to restore proper folding. If it is not successful, the UPR gives way to the apoptotic machinery.

Bulbar onset

The onset of ALS in the bulbar region: that is, the muscles of pharynx, tongue and larynx. The patient usually presents with speech and swallowing problems.

Intergenerational instability

This refers to the mechanism through which certain repeat expansions can increase in length during gametogenesis.

Somatic instability

Repeat expansions can grow longer in dividing cells. This explains why the length of an expansion can be variable between tissues and within cells within a tissue.

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Robberecht, W., Philips, T. The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci 14, 248–264 (2013). https://doi.org/10.1038/nrn3430

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