The Promise and Challenges of Developing miRNA-Based Therapeutics for Parkinson's Disease

Abstract

MicroRNAs (miRNAs) are small double-stranded RNAs that exert a fine-tuning sequence-specific regulation of cell transcriptome. While one unique miRNA regulates hundreds of mRNAs, each mRNA molecule is commonly regulated by various miRNAs that bind to complementary sequences at 3'-untranslated regions for triggering the mechanism of RNA interference. Unfortunately, dysregulated miRNAs play critical roles in many disorders, including Parkinson's disease (PD), the second most prevalent neurodegenerative disease in the world. Treatment of this slowly, progressive, and yet incurable pathology challenges neurologists. In addition to L-DOPA that restores dopaminergic transmission and ameliorate motor signs (i.e., bradykinesia, rigidity, tremors), patients commonly receive medication for mood disorders and autonomic dysfunctions. However, the effectiveness of L-DOPA declines over time, and the L-DOPA-induced dyskinesias commonly appear and become highly disabling. The discovery of more effective therapies capable of slowing disease progression -a neuroprotective agent-remains a critical need in PD. The present review focus on miRNAs as promising drug targets for PD, examining their role in underlying mechanisms of the disease, the strategies for controlling aberrant expressions, and, finally, the current technologies for translating these small molecules from bench to clinics.

Keywords: Parkinson’s disease; RNA interference; RNAi therapeutic; alpha-synuclein; gene silence; microRNA.

Figure 1

Biological synthesis of endogenous microRNAs (miRNAs) and modulation by synthetic oligonucleotides. miRNAs are coded in mammalian DNA genes and transcribed by RNA polymerase II (Pol II) to form the primary miRNA (pri-miRNA). This long RNA receives the first processing by Drosha and DGCR8 enzymes in cell nucleus, with remotion of nucleotides outside the hairpin. The resulting miRNA precursor (pre-miRNA) moves to cytoplasm carried by Exportin 5. Dicer and TRBP enzymes execute the second round of processing, resulting in miRNA duplexes with 18–25 nucleotides. Sense strand is removed. The guide (or antisense) strand is the mature miRNA that will guide the RISC complex (miRISC) to target mRNAs bearing partially complementary sequences in 3’-UTR region. Silencing of miRNA-targeted mRNAs occurs through translational repression or degradation. AGO—Argonaute 2; CDS—Coding sequence region of mRNA; 3’-UTR-3’ untranslated region; DGCR8—DiGeorge syndrome critical region gene 8; Dicer—a ribonuclease enzyme; Drosha—a ribonuclease enzyme; miRISC—RISC complex associated with a miRNA; Pol II—RNA polymerase II; pre-miRNA—miRNA precursor; pri-miRNA—primary miRNA; RISC—RNA-induced silencing complex; TRBP—HIV-1 Trans-activation response (TAR) RNA-binding protein. Reprinted with permission from Titze-de-Almeida and Titze-de-Almeida 2018, with modifications [34].

Figure 2

Schematic representation of miRNAs in the healthy and Parkinsonian brain. MicroRNAs expressed in the central nervous system contributes to brain development and cell physiology. Instead, aberrantly expressed miRNAs play a role in pathological mechanisms in a parkinsonian brain (PD brain). Translating to clinics, miRNAs are candidate biomarkers of disease progression and promising targets for miRNA-based therapeutics.