Aggregate leads

The genetic basis of amyotrophic lateral sclerosis is gradually being unpicked.

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neurone disease. It causes a relentlessly progressive muscle paralysis as motor neurones degenerate, and is invariably fatal. Around 10 per cent of cases run in families, with the remainder occurring sporadically. For the past 15 years mutations in just one gene, SOD1, have been linked to ALS, but SOD1 explains only a fraction of cases and the mechanisms of disease remained frustratingly unclear. In the past 18 months, Chris Shaw at King's College London and colleagues have identified two further genes that cause ALS when mutated, shedding more light on this distressing condition.

Inside the motor neurones of people with ALS are characteristic clumps of protein that have been tagged for recycling but have not been broken down. The main constituent of these clumps is a protein known as TDP-43, and in 2008 Professor Shaw's group discovered mutations in the gene encoding TDP-43, TARDBP, in a familial case of ALS (ref. 1). Screening for changes in this gene revealed mutations in one large family and two sporadic cases (ref. 2). Follow-up work by many other groups has confirmed that TARDBP mutations are a significant cause of ALS.

Although TDP-43 mutations are rare, TDP-43 protein is deposited in 90 per cent of all people with ALS and is the single biggest clue to the cause of motor neurone disease.

The discovery of TARDBP also led Professor Shaw's group to consider similar proteins as possible causes of ALS in other families. This hunch proved correct, with the subsequent identification of a mutation in a gene known as FUS (ref. 3). Screening other unexplained cases revealed a further seven families with FUS mutations. Normally, TDP-43 and FUS proteins are found in the nucleus. The effects of mutations in their respective genes are strikingly similar, both leading to large protein aggregations. The pathological effects of TDP-43 could be due to the build-up of toxic deposits in the cell, but equally could be due to loss of normal TDP-43 function in the nucleus.

The latest discoveries have provided powerful biological tools to explore underlying disease mechanisms and distinguish between these possibilities.

This research was supported by the Wellcome Trust and other funders.

Image: Chris Shaw of King's College London

References

1 Sreedharan J et al. Science 2008;319(5870):1668-72.
2 Rutherford NJ et al. PLoS Genet 2008;4(9):e1000193.
3 Vance C et al. Science 2009;323(5918):1208-11.