Interplay of RNA-Binding Proteins and microRNAs in Neurodegenerative Diseases

Abstract

The number of patients with neurodegenerative diseases (NDs) is increasing, along with the growing number of older adults. This escalation threatens to create a medical and social crisis. NDs include a large spectrum of heterogeneous and multifactorial pathologies, such as amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease and multiple system atrophy, and the formation of inclusion bodies resulting from protein misfolding and aggregation is a hallmark of these disorders. The proteinaceous components of the pathological inclusions include several RNA-binding proteins (RBPs), which play important roles in splicing, stability, transcription and translation. In addition, RBPs were shown to play a critical role in regulating miRNA biogenesis and metabolism. The dysfunction of both RBPs and miRNAs is often observed in several NDs. Thus, the data about the interplay among RBPs and miRNAs and their cooperation in brain functions would be important to know for better understanding NDs and the development of effective therapeutics. In this review, we focused on the connection between miRNAs, RBPs and neurodegenerative diseases.

Keywords: RNA-binding protein; microRNA; neurodegenerative disease.

Figure 1

Regulation of RBPs in miRNA biogenesis and processing. Pri-miRNAs are transcribed mainly by RNA polymerase II. The processing of pri-miRNA is mediated by a complex formed between Drosha and DGCR8, called Microprocessor, to generate pre-miRNA. TDP-43 facilitates the association of the Drosha complex with pri-miRNAs, whereas FUS and EWS promote Drosha recruitment to chromatin. HuR-mediated Msi2 binding to pri-miRNA inhibits Drosha cleavage. The function of hnRNP A1 is complexed, since it contributes to either the inhibition or stimulation of processing, which depends on the pri-miRNA. After pre-miRNAs are exported through the binding of Exportin-5 with RAN-GTP, pre-miRNAs are processed by Dicer. The processing of pre-miRNAs is facilitated by TDP-43 through the binding of Dicer with pre-miRNAs, whereas Dicer expression is negatively regulated by AUF1. On the other hand, TDP-43 negatively regulates the formation of miRISC from the Ago protein. PABP binds to the poly(A) region of target mRNA and promotes miRISC recruitment.