Will new understanding equal new treatments for toxic ALS mutation?

Will new understanding equal new treatments for toxic ALS mutation?

3139 2200 Peter Stevenson, PhD

Researchers may have solved the mystery surrounding the most common genetic cause of amyotrophic lateral sclerosis (ALS), marking out new territory in which to explore possible treatments.

ALS, also known as motor neuron disease (MND) or Lou Gehrig’s disease, is a degenerative neurological condition characterised by death of motor neurons responsible for voluntary control. Depending on the ALS variant, in time, patients with the disease are likely to lose their ability to walk, talk, swallow and breathe unaided. The disease is fatal and, currently, there is no cure.

The most commonly mutated gene in ALS is C9orf72, present in around 35% of cases. In healthy people, a segment of this gene is repeated up to 30 times, however, mutation leads to a dramatic increase in repeats, taking numbers into the thousands. This causes formation of dipeptide repeat polypeptides (DPRs) — repetitive proteins of abnormal length, which are known to be toxic to neurons.

But where does this toxicity come from? In a new report1, published April 10 in Molecular Cell, researchers from the St Jude Department of Structural Biology, Memphis, TN, USA, outlined that the toxicity of DPRs stems from their binding to key regions of nucleophosmin, a protein that is crucial in diverse cellular processes, such as regulation of tumour suppressors, cell proliferation and biogenesis of ribosomes — the complex molecular machines responsible for protein synthesis.

When DPRs bind to nucleophosmin, they block other important binding partners that are usually essential in maintaining the function of the nucleolus — a sort of biological assembly line found within the nucleus of a cell which, importantly, is responsible for creating ribosomes. As such, disruption of the nucleolus and, therefore, ribosomes, initiates a catastrophic process of decline.

The longer the DPR chain, the more severe the disruption/toxicity. “In the future, DPR length may have prognostic value for people with a diagnosis of ALS,” noted corresponding author Richard Kriwacki.2

“The work also provides a new direction for thinking about possible therapies to target toxic DPRs and their sites of action in patient cells,” stressed first author Michael White.2

Totally innovative approaches will be required to navigate the long road ahead, added Dr Kriwacki, but this fresh understanding has set the wheels in motion, he concluded2: “At least now we know what needs to be targeted.”


  1. White MR, Mitrea DM, Zhang P, Stanley CB, Cassidy DE, Nourse A. C9orf72 Poly(PR) Dipeptide Repeats Disturb Biomolecular Phase Separation and Disrupt Nucleolar Function. Mol Cell. 2019. doi: 10.1016/j.molcel.2019.03.019. [Epub ahead of print]
  2. Science Daily. Research reveals how the most common ALS mutation dooms cells. April 10, 2019.
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