Introduction
Parkinson’s disease (PD) is a chronic and progressive neurodegenerative
disorder that primarily affects the motor system (Bandopadhyay et al.,
2022). The depletion of dopamine-generating neurons in the brain
triggers symptoms such as shaking, rigidity, and challenges with
equilibrium and coordination (Mohammad Yasin Zamanian et al., 2023;
Mohammad Yassin Zamanian et al., 2023). Non-motor symptoms may also
occur, such as depression, anxiety, sleep disturbances, and cognitive
impairment (Ebina, Ebihara, & Kano, 2022; Mohammad Yassin Zamanian et
al., 2023). It is widely recognized that PD is a complex
neurodegenerative disorder with multiple underlying causes. Certain
mutations and genetic changes increase the risk of developing PD. About
3-5%of PD cases are caused by mutations in specific genes such as SNCA,LRRK2 , PRKN , PINK1 , and GBA , while 90
genetic risk variants account for 16-36% of the hereditary risk of the
sporadic form of PD (Bloem, Okun, & Klein, 2021). Exposure to certain
environmental factors is also an important cause of PD. These factors
may include being in contact with pesticides and herbicides, heavy
metals (such as lead and manganese), industrial chemicals, and certain
toxins. The development of PD has been associated with oxidative stress,
which occurs with an imbalance between reactive oxygen species (ROS)
production and the body’s capacity to detoxify them (Naren et al.,
2023). In addition, the accumulation of abnormal proteins, such as α-syn
and mitochondrial dysfunction are other processes that cause PD (Pang et
al., 2019).
The diagnosis is based on clinical signs, symptoms, and drug response,
and for atypical or complex cases relies primarily on testing with a low
accuracy (75-90%) due to the similarity of PD symptoms to other
neurodegenerative diseases. Understanding the events and pathways
driving PD onset and progression will shed light on potential targets
for diagnostic and possibly intervention strategies. Molecular
biomarkers can help differentiate PD from other disorders, leading to
more accurate diagnosis (Postuma & Lang, 2023). Biomarkers play a
critical role in PD research as they can provide insight into disease
pathology, aid in the diagnosis, and serve as targets for therapeutic
interventions (Surguchov, 2022; Voruz, Constantin, & Péron, 2022).
Since PD is primarily diagnosed based on clinical symptoms, biomarkers
can objectively measure disease progression and treatment response
(Zimmermann & Brockmann, 2022). Additionally, researchers and health
professionals use biomarkers to help diagnose disease, track its
progress, and evaluate the effectiveness of treatment (Valencia,
Ferreira, Merino-Torres, Marcilla, & Soriano, 2022). Several biological
molecules like a-synuclein, BDNF, and microRNAs (miRNAs) are being
explored for their biomarker potential in the early diagnosis of PD
(Emamzadeh & Surguchov, 2018; Khoo et al., 2012). Developments in
α-synuclein seed amplification assays have led to the potential of
differentiating PD patients from healthy controls. Looking at a new
study done by Siderowf et al., the assay can classify people with PD
with high sensitivity and specificity, presenting details about
molecular diversity and detecting affected people before diagnosis
(Siderowf et al., 2023). Recently, researchers used miRNAs as markers
for the detection and progression of PD and showed that several new
miRNAs have different expressions according to the diagnosis and
progression of PD (Elangovan et al., 2023; Emamzadeh & Surguchov,
2018). As research into biomarkers continues alongside the development
of iPSC and genome editing techniques such as the CRISPR-Cas9 method, it
is hoped that early and accurate diagnosis and treatment of PD will
become possible (Kumar et al., 2022; Rahman et al., 2022; Q. Sun et al.,
2022). CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic
Repeats/ CRISPR-associated protein 9) gene editing technology is a
powerful tool used for the precise manipulation of DNA in living
organisms. CRISPR refers to a set of DNA sequences that are derived from
bacteria and archaea (Pinjala et al., 2023). Cas9 is an enzyme that acts
as a molecular scissor and is guided by CRISPR RNA (crRNA) to target
specific DNA sequences (Chylinski, Le Rhun, & Charpentier, 2013;
Pinjala et al., 2023).
miRNAs are brief non-coding RNAs, approximately 22 nucleotides (about
21-25 nucleotides) in length, that regulate the post-transcriptional
network by identifying target-specific messenger RNA (mRNA) through base
pairing and either degrading the transcript or inhibiting mRNA
translation (Mouradian, 2012; Singh & Sen, 2017). miRNAs are important
contributors to cellular development and are involved in a range of
physiological processes, including cell growth, proliferation,
differentiation, aging, and programmed cell death (S. Li, Bi, Han, &
Huang, 2022). miRNAs are expressed in various types of nerve cells,
including neurons and glial cells (Xia et al., 2019). miRNAs are
involved in the regulation of neuronal development and play a role in
synaptic plasticity (Lagos-Quintana et al., 2002; Xia, Wang, & Zheng,
2020). miRNAs can control the expression of genes in charge of
neurotransmitter synthesis, release, and signaling pathways. They can
regulate the development and branching of dendrites by modulating the
expression of genes participating in cytoskeletal dynamics, membrane
trafficking, and signaling pathways (Antoniou et al., 2018; Rajman &
Schratt, 2017; Schratt, 2009; Song et al., 2012). Therefore, adult
neurons’ survival, function, and connectivity can be affected by a
disease-related decrease in miRNA biogenesis. Studies have shown that
deregulation of miRNAs is associated with numerous neurodegenerative
diseases, including Alzheimer’s disease (S. Liu et al., 2022),
amyotrophic lateral sclerosis (H. Liu et al., 2023), multiple sclerosis
(Sastri, Gupta, Kannan, Balamuralidhara, & Ramkishan, 2022), and PD
(Soto et al., 2023; S. K. Yadav et al., 2022). miRNAs are involved in
the regulation of epigenetic enzymes responsible for DNA methylation and
histone modifications (Uppala et al., 2023). For example, miR-29 family
members (miR-29a, miR-29b, and miR-29c) target DNA methyltransferases
(DNMTs) and downregulate their expression, resulting in global DNA
hypomethylation. miR-124 directly targets DNMT3b and downregulates its
expression, while also repressing EZH2, an enzyme involved in histone
methylation. miR-101a-3p negatively regulates DNMT3a, EZH2, and HDAC1,
leading to alterations in DNA methylation and histone modifications.
These miRNAs play a role in maintaining the balance of epigenetic
modifications and their dysregulation may contribute to PD pathogenesis.
In addition to their role in epigenetic regulation, miRNAs also target
PD-related proteins. For instance, miR-9 targets SIRT1, and its
inhibition enhances cell viability in PD models (Uppala et al., 2023).
Research in patients with PD and other neurodegenerative conditions
suggests that these patients have distinct tissue miRNA profiles (Leggio
et al., 2017; Martinez & Peplow, 2017; Quinlan, Kenny, Medina, Engel,
& Jimenez-Mateos, 2017). Blood derivatives are often analyzed for
biomarkers, and plasma is the preferred source over serum for studying
circulating miRNA. This is because the makeup of circulating miRNA may
change as a result of RNA released during coagulation (K. Wang et al.,
2012). In PD, several miRNAs are expressed differently compared to
healthy individuals (W. Ma et al., 2016; Scheper et al., 2023). miRNAs
have roles in the modulation of SNCA, PRKN (Parkin), and PTEN Induced
Kinase 1 (PINK1), which are all involved with PD. Additionally, miRNAs
affect the regulation of neuroinflammation and the survival of
dopaminergic neurons, which are specifically affected in PD (Moradi
Vastegani et al., 2023; Nies et al., 2021). miRNAs play a crucial role
in the regulation of mitochondrial dysfunction in PD (Tryphena et al.,
2022). Mitochondrial dysfunction is a major contributor to the
pathogenesis of PD, and miRNAs are dysregulated in PD patients (Tryphena
et al., 2022). The integration of miRNAs and nanotechnology holds great
promise for the treatment of PD. It enables targeted delivery of miRNAs
to the brain, allowing for precise modulation of disease mechanisms and
the potential for personalized medicine approaches (Tryphena et al.,
2023). The expression of PD-related genes and proteins may change as a
consequence of variations in miRNA expression. Specific miRNAs, such as
miR-126, miR-144, miR-204, and miR-221, have been involved in PD in
various studies (Gentile et al., 2022; J. Lu et al., 2017; Singh & Sen,
2017).
miR-221 was suggested to have a role in the development and progression
of various types of malignancies, such as breast cancer, pancreatic
cancer, and prostate cancer (Kawaguchi et al., 2013; Nassirpour, Mehta,
Baxi, & Yin, 2013; T. Sun et al., 2014). Ma et al. (W. Ma et al., 2016)
found that serum levels of miR-221 were positively correlated with the
UPDRS-V score, which is a measure of motor function in PD patients.
Furthermore, miR-221 can candidate as a marker for the diagnosis and
prognosis of PD (W. Ma et al., 2016). Additionally, miR-221 has been
discovered to impede cell apoptosis and help neuronal survival in PD (Oh
et al., 2018). Li et al. indicated that transient transfection of PC12
cells with miR-221 mimic led to a significant promotion of cell
viability and proliferation in the PD cell models. This suggests that
miR-221 may increase the survival and proliferation of PC12 cells (L.
Li, Xu, Wu, & Hu, 2018).
In this review, we will examine recent preclinical and clinical data on
the emerging function of miR-221 in the pathophysiology of PD. This
investigation aims to investigate the role of miR-221 in PD and its
prospect as a therapeutic target.