Drug Discovery Opinion

Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, is one of the most common neuromuscular diseases worldwide. The disease results in progressive loss of motor neurones leading to muscle weakening and atrophy, and is usually fatal within 5 years of the onset of symptoms. Most cases (90-95%) of ALS are sporadic with no evidence of inheritance but 5-10% of cases are familial and do have a hereditary component. Familial ALS has been linked to mutations in a number of genes including those encoding superoxide dismutase (SOD1) (~20% of familial cases), TAR DNA binding protein and, most recently, FUS (fused in sarcoma) protein (~5% of familial cases). The FUS protein is believed to be involved in DNA repair and transcription as well as RNA splicing and transport of RNA from the nucleus to the cytoplasm. Although normal FUS protein is largely confined to the nucleus, mutated FUS protein forms aggregates in the cytoplasm and these deposits have been correlated with degeneration of nerve cells.

Researchers from Northwestern University Feinberg School of Medicine have now shown that FUS protein forms characteristic skein-like cytoplasmic inclusions in spinal motor neurones in most cases of ALS, not just familial cases. Post-mortem examination of spinal cords and brains from 78 ALS sufferers and 22 controls showed that FUS pathology was present in all the ALS samples (except for those from patients with SOD1 mutations) but not in the control samples.

Although mutations in FUS account for only a small fraction of ALS, the study suggests that FUS protein may be a common component of the cellular inclusions in non-SOD1 ALS, whether familial or sporadic. Although the cause of ALS remains unknown, the identification of a common pathway in familial and sporadic ALS may spur the development of new cell-based and animal models of disease, and could eventually lead to new therapies for motor neurone diseases.

The study is published in the Annals of Neurology.