Figure 1. Biogenesis of miR-221/222. The process starts with the transcription of the miR-221/222 gene into a primary transcript called pri-miR-221/222 by RNA polymerase II. This primary transcript is then broken by the nuclear RNase Drosha, creating the formation of a stem-loop precursor called pre-miR-221/222 in the nucleus. The exportin-5 transporter then moves the pre-miR-221/222 out of the nucleus and into the cytoplasm. In the cytoplasm, the endoribonuclease Dicer cleaves the pre-miR-221/222 into a double-stranded miRNA duplex. Finally, an AGO protein family member gets attached to the mature miRNAs to form the RISC, which is involved in regulating protein expression and various biological events.
On the other hand, other miRNAs are involved in PD. The decrease in miR-7 levels contributes to the increase of α-syn in PD through its regulatory role in gene expression. miR-7 is known to bind to the 3’ UTR of the α-syn Non-A4 Component of Amyloid Precursor (SNCA) gene and inhibit its translation. In patients with PD, there is a significant reduction in the levels of mature miR-7 in the substantia nigra, which leads to a decrease in its inhibitory effect on α-syn expression. This reduction in miR-7 allows for increased translation of the SNCA gene and subsequent accumulation of α-syn protein. Therefore, the decrease in miR-7 levels disrupts the normal regulation of α-syn expression, leading to its accumulation and the characteristic pathology observed in PD (McMillan et al., 2017).
miR-153 plays a role in the post-transcriptional regulation of SNCA expression, which is central to the pathogenesis of PD. miR-153 binds specifically to the 3-UTR of SNCA mRNA and down-regulates its mRNA and protein levels 3. miR-153 is expressed predominantly in the brain and shows a pattern that mirrors SNCA expression in different tissues and during neuronal development. The levels of miR-153 correspond to the expression of SNCA mRNA, with high levels of SNCA mRNA associated with increased levels of mir-153 expression. These findings suggest that miR-153 plays a tuning role in the amount of SNCA produced and may be involved in regulating fluctuations in endogenous SNCA protein levels (Doxakis, 2010).
miR-34b/c refers to a group of miRNAs that includes miR-34b and miR-34c. The downregulation of miR-34b/c in PD brains has been shown to have a significant impact on mitochondrial function and cellular viability. In experiments using differentiated SH-SY5Y dopaminergic neuronal cells, depletion of miR-34b or miR-34c resulted in a moderate reduction in cell viability. This decrease in viability was accompanied by altered mitochondrial function and dynamics, oxidative stress, and a reduction in intracellular ATP content. Specifically, the depletion of miR-34b or miR-34c led to a decrease in the expression of DJ1 and Parkin, two proteins associated with familial forms of PD that also have a role in idiopathic cases. The reduction in DJ1 and Parkin expression was coupled with impaired mitochondrial function, as evidenced by a diminished capability of mitochondria to reduce MTT and a significant loss in mitochondrial membrane potential. Furthermore, the depletion of miR-34b or miR-34c resulted in increased production of ROS and decreased intracellular ATP levels (Minones-Moyano et al., 2011). Overall, the downregulation of miR-34b/c in PD brains compromises mitochondrial function and dynamics, leading to oxidative stress and a decrease in cellular viability.
miR-4639-5p is a microRNA that has been identified as a regulator of DJ-1 expression in PD. DJ-1 is a protein that plays a crucial role in protecting cells against oxidative stress. Chen et al. found that abnormal up-regulation of miR-4639-5p in PD patients leads to a decrease in DJ-1 protein levels. This decrease in the DJ-1 protein level results in severe oxidative stress and neuronal death. They also showed that miR-4639-5p directly binds to the 3’-UTR of the DJ-1 mRNA, which leads to the repression of DJ-1 protein expression. This indicates that miR-4639-5p post-transcriptionally regulates DJ-1 expression by affecting the translation of DJ-1 mRNA (Chen et al., 2017).
miR-137 is a microRNA that has been shown to play a vital role in the induction of oxidative stress in neurons in PD. Jiang et al. reported that miR-137 is upregulated in PD and targets a gene called oxidation resistance 1 (OXR1). OXR1 is known to have protective effects against oxidative stress-induced neurodegeneration. In PD, there is an imbalance between the production of ROS and cellular antioxidant activity, leading to oxidative stress. miR-137, by targeting and downregulating OXR1, disrupts the balance between ROS production and antioxidant activity, thereby contributing to the induction of oxidative stress in neurons in PD (Jiang et al., 2019). Furthermore, they showed that inhibition of exosomal miR-137, which is derived from serum, can alleviate oxidative stress injury in PD by upregulating OXR1 3. This suggests that targeting miR-137 or manipulating its levels in exosomes could be a potential therapeutic strategy for PD treatment (Jiang et al., 2019). In summary, miR-137 contributes to the induction of oxidative stress in neurons in PD by targeting and downregulating OXR1, which disrupts the balance between ROS production and antioxidant activity.