ReviewMicroRNAs in Parkinson's disease
Introduction
Parkinson's disease (PD) is a progressive age-dependent neurodegenerative disorder that affects an estimated 1% of the population over 50. It is characterized clinically by resting tremor, bradykinesia, cogwheel rigidity, and postural instability (Savitt et al., 2006). In Blocq and Marinesco (1893) reported their findings from the autopsy of a 38 years old patient with unilateral Parkinsonism. They described a 2–5 cm lesion in the contra-lateral half of the mid-brain that destroyed the right substantia nigra (SN) and nearby parts of the ventral tegmentum. Thereafter, cumulative evidence confirmed that loss of dopaminergic neurons in the SN pars compacta, which results in loss of dopamine in the striatal projections of these neurons, underlies the motor syndrome of PD. Pathologically, PD is characterized by intraneuronal inclusions called lewy bodies containing abnormal aggregates of the presynaptic protein α-synuclein as their main component. While PD is mainly a sporadic disease, several genes have been linked to the rare monogenic forms of the disease such as α-synuclein, leucine-rich repeat kinase 2 (LRRK2), parkin, PTEN-induced kinase 1 (PINK1) and DJ-1. Recent evidence indicates that dysfunction of these pathways play a direct role in the etiology of the sporadic form of the disease as well. For a more detailed discussion of the molecular pathogenesis of PD, the reader is referred to more in depth reviews (Dawson and Dawson, 2003, Gasser, 2009).
Since the description of PD by James Parkinson in 1817 (Parkinson, 1817), the only therapeutic breakthrough was made in the 1960s by the use of Levodopa to replace endogenous dopamine deficiency (Cotzias, 1968). Despite the major strides made in our understanding of the pathophysiology of the disease, our ability to intervene remains stagnant at symptomatic management. Recent characterization of druggable molecules such as microRNAs carries therapeutic potential for complex disease processes such as PD. In this article, we review the current evidence in the literature linking the miRNA pathway to PD pathophysiology.
The discovery of microRNAs (miRNAs) 10 years ago uncovered a complex layer of post-transcriptional regulation of gene expression (Lagos-Quintana et al., 2001, Lau et al., 2001, Lee and Ambros, 2001). MicroRNAs are small non-coding regulatory molecules that are important in multiple physiologic and disease processes such as stem cell biology and neurodegeneration. Due to their small size and relative ease of delivery, miRNAs are promising therapeutic tools/targets in major diseases such as cancer, cardiovascular diseases and neurodegenerative disorders.
MiRNAs are transcribed by RNA polymerase II into a primary transcript (pri-miRNA) forming a self-folded hairpin structure, which is recognized and processed by the Drosha/DGCR8 enzyme complex into a ∼70 base pair (bp) long precursor miRNA (pre-miRNA). Pre-miRNAs are actively transported from the nucleus to the cytoplasm where they are further processed by dicer into a ∼23 bp double stranded miRNA/miRNA*. One strand (sometimes each strand) is incorporated into the RNA-induced silencing complex (RISC), which contains an argonaute (Ago) family member protein as a core component. Mature miRNAs guide RISC to recognize their target mRNAs through partial complementarity to target sequences localized mostly in the 3′UTR, which lead to mRNA degradation or translation repression (Bartel, 2009).
Recent evidence suggests that translation regulation is an important process in the pathophysiology of PD. For example, post-transcriptional regulation of protein expression levels was linked to DJ-1 in sporadic PD (Blackinton et al., 2009). Another study demonstrated that overexpression of the translation inhibitor Thor (Drosophila homolog of mammalian eukaryotic initiation factor 4E-binding protein; 4E-BP) inhibits the abnormal phenotypes as well as limits dopaminergic neurons loss in parkin and PINK1 Drosophila models of PD (Tain et al., 2009). In addition, genetic and biochemical evidence suggest that LRRK2 modulates the maintenance of DA neurons by regulating protein synthesis through phosphorylation of 4E-BP. This phosphorylation seems important in mediating the pathogenicity of mutant Drosophila LRRK (Imai et al., 2008). These studies emphasize the emerging role of post-transcriptional regulation of protein expression in PD. In this review we focus on the miRNA mediated translation regulation relevant to PD pathophysiology.
Section snippets
Differential miRNA expression in Parkinson's disease
Abeliovich and his colleagues carried out miRNA profiling using qPCR in RNA samples from PD patients and normal controls. Among a panel of 224 precursor miRNAs, 8 were enriched in midbrain; pre-let7a-1, pre-miR7-2, -99a, -130, -133b, -136, -224, and -143. Notably, pre-miR-133b was downregulated in PD samples more than 6 times. Several other pre-miRNA were expressed in high levels in the midbrain and downregulated significantly in PD samples such as pre-miR-218-2, -15b, -101-1, -107, -335, -345.
Concluding remarks
Emerging evidence strongly indicate a major role for translational regulation in PD pathophysiology. The miRNA pathway is one of the major translation regulation pathways. Multiple miRNAs have been linked to PD (Table 1) opening new avenues for therapeutic targets. While translational applications of research findings in the field are still to be developed, lessons learned from miRNA use as biomarkers and therapeutic targets in cancer research pave the way for PD applications development.
Disclosures
The authors declare no conflicts of interest.
Author contributions
M.M.H prepared a draft of the article. T.M.D and V.L.D revised the article. All authors have approved the final article.
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