Altered RNA metabolism and amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults. Typically, patients with ALS develop progressive weakness resulting, eventually, in respiratory muscle paralysis and death in 3-5 years after the onset of the disease. No definite therapy currently exists for ALS. The biologic basis of the disease is unknown. However, ALS research has taken a dramatic turn over the last 3 years. Landmark discoveries of mutations in the transactive response DNA-binding protein (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS) as causative of ALS and demonstration that abnormal aggregation of these proteins is the proximate cause of motor neuron loss in familial and sporadic ALS have initiated a paradigm shift in understanding the pathogenic mechanism of this disease. TDP-43 and FUS/TLS are DNA/RNA-binding proteins with striking structural and functional similarities. This article reviews the current direction of research efforts toward understanding the role of RNA (ribonucleic acid) processing regulation in ALS and possible therapeutic pathways in this fatal disease.