Macro roles for microRNAs in neurodegenerative diseases

Abstract

Neurodegenerative diseases (NDs) are typically adult-onset progressive disorders that perturb neuronal function, plasticity and health that arise through a host of one or more genetic and/or environmental factors. Over the last decade, numerous studies have shown that mutations in RNA binding proteins and changes in miRNA profiles within the brain are significantly altered during the progression towards NDs - suggesting miRNAs may be one of these contributing factors. Interestingly, the molecular and cellular functions of miRNAs in NDs is largely understudied and could remain a possible avenue for exploring therapeutic treatments for various NDs. In this review, I describe findings which have implicated miRNAs in various NDs and discuss how future studies focused around miRNA-mediated gene silencing could aid in furthering our understanding of maintaining a healthy brain.

Fig. 1

MiRNA biogenesis. miRNAs are transcribed from the genome by RNA polymerases II or III as primary-miRNA (Pri-miRNA). Pri-miRNAs are modified by a cap structure and polyadenylation. The pri-miRNA is processed in the nucleus by the Drosha/DGCR8 microprocessor complex which crops the pri-miRNA into a shorter hairpin-shaped precursor-miRNA (Pre-miRNA). The pre-miRNA is exported to cytoplasm via Exportin-5 and processed by Dicer which removes the hairpin. Next, one of the strands of the miRNA duplex is incorporated into Argonaute (AGO) proteins to form the miRNA inducing silencing complex (miRISC), which silences the mRNA via translational repression or by mRNA degradation.

Fig. 2

MiRNAs involved in the pathogenesis of Alzheimer's disease (AD). A) miRNAs which repress expression of APP or APP metabolizing enzymes are down-regulated in AD, leading to enhanced translation of BACE and PSEN. Additionally, Ab plaques further reduce expression of BACE and PSEN targeting miRNAs. miR-107, miR-9, miR-101 and miR-153 are shown as examples. B) miRNAs regulate Tau synthesis and formation of Neurofibrillary Tangles (NFTs). Both NFTs and Ab plaques contribute to the loss of synapses and neuronal death associated with AD. miR-9 and miR-34 are shown as examples.

Fig. 3

MiRNAs involved in the pathogenesis of Parkinson's disease (PD). miRNAs which repress expression of a-synuclein (a-SYN) are down-regulated in PD, leading to enhanced translation and aggregation of a-SYN. a-SYN aggregates are not cleared by normal cellular degradation machineries, often because miRNA-mediated silencing events which regulate translation of proteins involved in a-SYN clearance are also disrupted in PD. miR-7, miR-153 and miR-34 b/c target a-SYN. miR-16-1 targets HSP70. miR-224, miR-320a, miR-373 and miR-379 target LAMP2A.