microRNAs in Parkinson's Disease: From Pathogenesis to Novel Diagnostic and Therapeutic Approaches

Abstract

Parkinson's disease (PD) is the most prevalent central nervous system (CNS) movement disorder and the second most common neurodegenerative disease overall. PD is characterized by the progressive loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) within the midbrain, accumulation of alpha-synuclein (α-SYN) in Lewy bodies and neurites and excessive neuroinflammation. The neurodegenerative processes typically begin decades before the appearance of clinical symptoms. Therefore, the diagnosis is achievable only when the majority of the relevant DAergic neurons have already died and for that reason available treatments are only palliative at best. The causes and mechanism(s) of this devastating disease are ill-defined but complex interactions between genetic susceptibility and environmental factors are considered major contributors to the etiology of PD. In addition to the role of classical gene mutations in PD, the importance of regulatory elements modulating gene expression has been increasingly recognized. One example is the critical role played by microRNAs (miRNAs) in the development and homeostasis of distinct populations of neurons within the CNS and, in particular, in the context of PD. Recent reports demonstrate how distinct miRNAs are involved in the regulation of PD genes, whereas profiling approaches are unveiling variations in the abundance of certain miRNAs possibly relevant either to the onset or to the progression of the disease. In this review, we provide an overview of the miRNAs recently found to be implicated in PD etiology, with particular focus on their potential relevance as PD biomarkers, as well as their possible use in PD targeted therapy.

Keywords: biomarkers; exosomes; microRNAs; neuroprotective therapies; parkinson’s disease.

Figure 1

Biogenesis pathways of microRNAs and their dysregulations in Parkinson’s disease (PD). On the left panel, schematic representation of the intracellular miRNA canonical biogenesis, starting with transcription of pri-miRNA. The pri-miRNA is processed in the nucleus to pre-miRNA by the microprocessor complex (Drosha and DGCR8). The pre-miRNA is then exported via Exportin-5 into the cytoplasm where it is further cleaved by Dicer. Finally, the mature guide strand is assembled with members of the Argonaute family to form a functional RNA-induced silencing complex (RISC). On the right panels, ablation of DGCR8 (human) and its effect on brain (top right) and temporal and spatial controlled ablation of Dicer (mouse) and its effect on different brain areas (bottom right). knockout (KO); ventral tegmental area (VTA); coding sequence (CDS); substantia nigra pars compacta (SNpc).

Figure 2

Regulation of PD-related genes mediated by miRNAs. Schematic representation of miRNA-mediated dysfunction networks in PD-related genes. Inhibitory arrows indicate how miRNAs act on their target sequence. Red crosses on inhibitory arrows indicate PD-related pathogenic processes blocking miRNA binding on their targets. Red crosses on miRNA target binding sites indicate an SNP interfering with the direct miRNA binding on their specific target sequence. Green and red thick arrows indicate, respectively, an upregulation or downregulation of a given miRNA or protein.

Figure 3

Development of miRNA-based therapies for PD treatment. The three panels on the top left show the mechanisms of action of endogenous miRNAs (in black), miRNA mimics (in red) and antago-miRs (in green). Mimics are able to bind their target sequence, thus mimicking the effects of the corresponding endogenous miRNA (in red the inhibitory arrow indicating their effect on the specific target sequence). On the contrary, the antago-miRs bind and block the specific endogenous miRNAs, which are, consequently, unable to bind the target sequence. The top central panel shows the most used chemical modifications stabilizing miRNA mimics and antago-miRs backbones. On the top right panel the main delivery methods used to carry miRNA mimics and antago-miRs across the BBB (i.e., viral vectors, liposomes, polymeric nanoparticles and exosomes). On the low-bottom panel, four miRNAs potentially useful as new therapeutics and their functional effects in the context of PD.