Figure 1.

Schematic representation of the potential regulation of RNA homeostasis by abnormal energy metabolism in amyotrophic lateral sclerosis (ALS). Dysregulated energy homeostasis might result from dysregulation of mitochondrial function, which has been well documented in ALS pathogenesis (1). Many ALS- associated genes (including TDP-43, FUS/TLS and C9ORF72) have been implicated in the regulation of mitochondrial functions and RNA metabolism, thus suggesting that altered mitochondrial functions and RNA toxicity might contribute to ALS pathogenesis. In addition, dysfunction of energy-regulating proteins may also contribute to dysregulated energy homeostasis in ALS (2). Specifically, recent studies suggest that abnormal cellular energy status in ALS enhances activity of an energy sensor (AMP kinase, AMPK) that interferes with the transport of several RNA-binding proteins (RBPs) into nuclei of motor neurons, which might be one of the early events in ALS pathogenesis. The impaired transport of nuclear RBPs might disrupt cellular RNA homeostasis. Moreover, reactive oxygen species (ROS) production might also cause the abnormal activation of energy regulating proteins (3), and subsequently led to the mislocalization of RBPs. Further investigation is required to delineate the potential regulation of RNA homeostasis by energy dysfunction, to explore the key players involved in such regulation, and to consolidate the role of such abnormality in ALS pathogenesis. See text for additional details.