Implications of microRNA dysfunction in the pathogenesis of ALS

Recent studies have identified mutations in the genes encoding TDP-43 and FUS/TLS in patients with amyotrophic lateral sclerosis (ALS). Both TDP-43 and FUS/TLS display all the characteristics of a heterogeneous nuclear ribonucleoprotein, which regulates various aspects of RNA processing. In addition, TDP-43 is partly cleared from the nuclei of neurons containing cytoplasmic aggregates, suggesting loss of normal TDP-43 function in the nucleus, leading to defects or alterations in RNA metabolism, plays, at least in part, a causative role in the pathogenesis of ALS. TDP-43 has been reported to be involved in the Drosha complex required for the biogenesis of microRNAs. The high expression level of microRNAs and the exclusive expression of certain microRNAs in the central nervous system highlights their biological importance at all stages of neural development as well as in differentiated neurons. In addition, the altered expression of certain microRNAs has been implicated in the pathogenesis of neurodegenerative diseases. Therefore, elucidation of the role of TDP-43 in microRNA biogenesis as a component of the Drosha complex is indispensable to understanding pathophysiology of ALS. In addition, the identification of TDP-43-regulated microRNAs associated with motor neuron death is expected to further contribute to the development of novel therapeutic strategies for ALS treatment.