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.