MicroRNAs and neurodegeneration: role and impact

Abstract

Neurodegenerative diseases are typically late-onset, progressive disorders that affect neural function and integrity. Although most attention has been focused on the genetic underpinnings of familial disease, mechanisms are likely to be shared with more predominant sporadic forms, which can be influenced by age, environment, and genetic inputs. Previous work has largely addressed the roles of select protein-coding genes; however, disease pathogenesis is complicated and can be modulated through not just protein-coding genes, but also regulatory mechanisms mediated by the exploding world of small non-coding RNAs. Here, we focus on emerging roles of miRNAs in age-associated events impacting long-term brain integrity and neurodegenerative disease.

Figure 1. The miRNA biogenesis pathway

The biogenesis of a miRNA starts with the transcription of the primary (pri-miRNA) by RNA Polymerase II. The pri-miRNA is cleaved by the microprocessor complex (Drosha/DGCR8 in vertebrates, Drosha/Pasha in Drosophila) to generate the precursor miRNA (pre-miRNA). The pre-miRNA is transported to the cytoplasm, then cleaved by the Dicer/TRBP (Dicer/Loqs in Drosophila) complex to generate the miRNA duplex. After incorporation into miRISC and strand selection, the mature miRNA strand induces translational repression and/or mRNA cleavage, leading to reduction of the protein.

Figure 2. Ways by which miRNA pathways impact neurodegenerative disease

(A) miRNAs, which can be altered in disease, may directly target disease-related transcripts, to alter their translation or level. (B) Evidence also suggests that some disease-related proteins, such as HTT and TDP-43, may directly affect miRNA biogenesis or miRNA target silencing activity.