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\begin{document}

\title{miR-221 and Parkinson's disease: A biomarker with therapeutic potential}



\author[1]{Mohammad Yassin Zamanian}%
\author[2]{Mehraveh  Sadeghi Ivraghi}%
\author[3]{Reena   Gupta}%
\author[4]{KDV   Prasad }%
\author[5]{Hashem  Alsaab}%
\author[6]{Beneen   Hussien}%
\author[7]{Hazem Ahmed}%
\author[8]{Montather   Ramadan}%
\author[9]{Maryam   Golmohammadi}%
\author[10]{Nikta   Nikbakht}%
\author[11]{Tuba  Oz }%
\author[11]{Małgorzata  Kujawska }%
\affil[1]{Hamadan University of Medical Sciences}%
\affil[2]{Qazvin University of Medical Sciences}%
\affil[3]{GLA University}%
\affil[4]{Symbiosis International (Deemed University)}%
\affil[5]{Taif University}%
\affil[6]{The Islamic University }%
\affil[7]{Al-Farahidi University}%
\affil[8]{Al-Ayen University}%
\affil[9]{Shahid Beheshti University of Medical Sciences}%
\affil[10]{Hamedan University of Medical Sciences}%
\affil[11]{Poznan University of Medical Sciences}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Parkinson's disease (PD) is a neurodegenerative disorder characterized
by the loss of dopaminergic neurons in the substantia nigra, leading to
various motor and non-motor symptoms. Several cellular and molecular
mechanisms such as alpha-synuclein (\selectlanguage{greek}α-\selectlanguage{english}syn) accumulation, mitochondrial
dysfunction, oxidative stress, and neuroinflammation are involved in the
pathogenesis of this disease. MicroRNAs (miRNAs) play important roles in
post-transcriptional gene regulation. They are typically about 21-25
nucleotides in length and are involved in the regulation of gene
expression by binding to the messenger RNA (mRNA) molecules. miRNAs like
miR-221 play important roles in various biological processes, including
development, cell proliferation, differentiation, and apoptosis. miR-221
is also implicated in promoting neuronal survival against oxidative
stress and in promoting neurite outgrowth and neuronal differentiation.
Additionally, the role of miR-221 in PD has been investigated in several
studies. According to the results of this study; 1) miR-221 protects
against oxidative stress in 6-hydroxydopamine-induced PC12 cells; 2)
miR-221 prevents Bax/caspase-3 signaling activation by stopping Bim; 3)
miR-221 has moderate predictive power for PD; 4) miR-221 directly
targets PTEN, and PTEN over-expression eliminates the protective action
of miR-221 on p-AKT expression in PC12 cells; 5) miRNA-221, by
manipulating the Akt signaling pathway, performs in controlling cell
viability and apoptosis in PD. This review study suggests that miR-221
has the potential to be used as a clinical biomarker for PD diagnosis
and stage assignment.%
\end{abstract}%



\sloppy


\textbf{miR-221 and Parkinson's disease: A biomarker with therapeutic
potential}

Mohammad Yasin Zamanian\textsuperscript{1,2}, Mehraveh Sadeghi
Ivraghi\textsuperscript{3}, Reena Gupta\textsuperscript{4}, KDV
Prasad\textsuperscript{5, 6}, Hashem O. Alsaab\textsuperscript{7},
Beneen M. Hussien\textsuperscript{8}, Hazem Ahmed\textsuperscript{9},
Montather F. Ramadan\textsuperscript{10}, Maryam
Golmohammadi\textsuperscript{11*}, Nikta Nikbakht\textsuperscript{12*},
Tuba Oz\textsuperscript{13}, and Ma\selectlanguage{polish}ł\selectlanguage{english}gorzata Kujawska\textsuperscript{13}

\textsuperscript{1}Neurophysiology Research Center, Hamadan University
of Medical Sciences, Hamadan 6718773654, Iran.

\textsuperscript{2}Department of Physiology, School of Pharmacy, Hamadan
University of Medical Sciences, Hamadan 6718773654, Iran.

\textsuperscript{3}School of Medicine, Qazvin University of Medical
Sciences, Qazvin, Iran.

\textsuperscript{4}Institute of Pharmaceutical Research, GLA University,
District-Mathura, U. P., India.

\textsuperscript{5}Symbiosis Institute of Business Management (SIBM),
Hyderabad, India

\textsuperscript{6}Symbiosis International (Deemed University) (SIU) Off
Bangalore Highway Kothur Mandal Village, Mahabubnagar, Hyderabad,
Telangana, India.

\textsuperscript{7}Pharmaceutics and Pharmaceutical Technology, Taif
University, Taif, Saudi Arabia

\textsuperscript{8}Medical Laboratory Technology Department, College of
Medical Technology, The Islamic University, Najaf, Iraq.

\textsuperscript{9} Medical Technical College, Al-Farahidi University,
Baghdad, Iraq.

\textsuperscript{10}College of Dentistry, Al-Ayen University, Thi-Qar,
Iraq. 

\textsuperscript{11}School of Medicine, Shahid Beheshti University of
Medical Sciences, Tehran 198887355.

\textsuperscript{12}Department of Physical Medicine and Rehabilitation,
School of Pharmacy, Hamadan University of Medical Sciences, Hamadan
6718773654, Iran.

\textsuperscript{13} Department of Toxicology, Poznan University of
Medical Sciences, Dojazd 30, Pozna\selectlanguage{polish}ń, \selectlanguage{english}Poland.

* \textbf{Corresponding Authors:}

-Dr. Maryam Golmohammadi, School of Medicine, Shahid Beheshti University
of Medical Sciences, Tehran, Iran; Tel: +989187018850; Email Address:
maryam.golmohammadi.sbmu@gmail.com

-Dr. Nikta Nikbakht, Department of Physical Medicine and Rehabilitation,
School of Pharmacy, Hamadan University of Medical Sciences, Hamadan
6718773654, Iran. Email Address: drniktanikbakht@gmail.com

\textbf{Abstract}

Parkinson's disease (PD) is a neurodegenerative disorder characterized
by the loss of dopaminergic neurons in the substantia nigra, leading to
various motor and non-motor symptoms. Several cellular and molecular
mechanisms such as alpha-synuclein (\selectlanguage{greek}α-\selectlanguage{english}syn) accumulation, mitochondrial
dysfunction, oxidative stress, and neuroinflammation are involved in the
pathogenesis of this disease. MicroRNAs (miRNAs) play important roles in
post-transcriptional gene regulation. They are typically about 21-25
nucleotides in length and are involved in the regulation of gene
expression by binding to the messenger RNA (mRNA) molecules. miRNAs like
miR-221 play important roles in various biological processes, including
development, cell proliferation, differentiation, and apoptosis. miR-221
is also implicated in promoting neuronal survival against oxidative
stress and in promoting neurite outgrowth and neuronal differentiation.
Additionally, the role of miR-221 in PD has been investigated in several
studies. According to the results of this study; 1) miR-221 protects
against oxidative stress in 6-hydroxydopamine-induced PC12 cells; 2)
miR-221 prevents Bax/caspase-3 signaling activation by stopping Bim; 3)
miR-221 has moderate predictive power for PD; 4) miR-221 directly
targets PTEN, and PTEN over-expression eliminates the protective action
of miR-221 on p-AKT expression in PC12 cells; 5) miRNA-221, by
manipulating the Akt signaling pathway, performs in controlling cell
viability and apoptosis in PD. This review study suggests that miR-221
has the potential to be used as a clinical biomarker for PD diagnosis
and stage assignment.

Keywords: Biomarkers; Neuroprotection; Parkinson's disease; miR-221

\textbf{Graphical abstract:} miR-221 has been found to have a protective
role by regulating oxidative stress. In a cellular model of Parkinson's
disease induced by 6-OHDA, miR-221 was shown to inhibit apoptosis and
promote cell viability and proliferation. Furthermore, miR-221 was found
to target the PTEN gene, which is involved in regulating the AKT/mTOR
signaling pathway. Overexpression of miR-221 led to increased
phosphorylation of AKT, indicating activation of this pathway.

\textbf{Abbreviations}

AKT: Protein kinase B

BAX: Bcl-2-associated X protein

BDNF: Brain-derived neurotrophic factor

BMF: Bone marrow failure

BNIP3L: BCL2/adenovirus E1B 19-kDa-interacting protein 3-like

CDKN1B: Cyclin-dependent kinase inhibitor 1B

CRISPR: Clustered regularly interspaced short palindromic repeats

DGCR8: DiGeorge Critical Region 8

DJ-1: Parkinson's disease protein 7

FOXO: Forkhead box transcription factors

GBA: Glucocerebrosidase

HOTAIR: HOX antisense intergenic RNA

iPSC: Induced pluripotent stem cells

LRRK2: Leucine-rich repeat kinase 2

mTOR: mammalian target of rapamycin

MYC: Myelocytomatosis

NPTX2: Neuronal pentraxin-2

PARK2: Parkin RBR E3 ubiquitin-protein ligase

PD: Parkinson's disease

PI3K: Phosphoinositide 3-kinases

PINK1: PTEN-induced kinase 1

PRKN: Parkin RBR E3 Ubiquitin Protein Ligase

PTEN: Phosphatase and tensin homolog

ROS: Reactive oxygen species

SNCA: Synuclein Alpha

SNHG1: Small nucleolar RNA host gene 1

Sp1: Specificity protein 1

TMEM87A: Transmembrane protein 87A

UPDRS: Unified Parkinson's disease rating scale

\textbf{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,\emph{LRRK2} , \emph{PRKN} , \emph{PINK1} , and \emph{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 \selectlanguage{greek}α-\selectlanguage{english}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, \& P\selectlanguage{ngerman}éron, 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
\selectlanguage{greek}α-\selectlanguage{english}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.

\textbf{Overview of miR-221}

Numerous studies indicated that miRNAs are especially abundant in the
nervous system, and play a part in maintaining efficient mammalian brain
function. miRNAs have a unique cellular or tissue expression profile in
response to the nervous system (L. Zhao \& Wang, 2019a). miRNAs
typically bind to the 3' untranslated region (UTR) of target mRNAs,
leading to post-transcriptional regulation of gene expression.
Repression of mRNA translation or degradation is the result of this
interaction, which depends on the degree of complementarity between
miRNA and its target mRNA (Di Martino et al., 2022).

miR-221 was first identified in 2002 by Lagos-Quintana and colleagues as
a small non-coding RNA molecule that is highly expressed in human
endothelial cells (Lendeckel). Various cellular mechanisms, such as cell
proliferation, differentiation, and apoptosis, are regulated by miR-221,
which is involved in numerous diseases, including cancer and
cardiovascular disease (Eyermann, Czaplinski, \& Colognato, 2012;
Garofalo \& Croce, 2011; Im \& Kenny, 2012). In human DNA, the miR-221
is a gene cluster located on chromosome Xp11.3, which is transcribed
together with miR-222 as primary miRNA (pri-miR)-221/222. They have the
same seed sequence and are 726 base pairs far apart. The promoter of
pri-miR-221/222 is located in the intergenic region between the CDKN1B
and TMEM87A genes on chromosome Xp11.3 in humans (Fornari et al., 2008;
Visone et al., 2007). The promoter region has several binding sites for
transcription factors, including E2F, SP1, and MYC, which are involved
in the regulation of pri-miR-221/222 expression. Additionally, there are
three poly-A sequences found downstream of pre-miR-221 and two types of
canonical TATA boxes at 550 and 190 bp upstream of pre-miR-222 in the
miR-221/222 promoter region. Pre-miR-221 and pre-miR-222 are created as
a result of the nuclear processing of pri-miR-221/222 that is mediated
by Drosha and the RNA-binding protein DGCR8. These two miRNAs are 110
nucleotides long and are transported out of the nucleus by the
exportin-5 transporter. Dicer cleaves the miR-221 molecule into its
mature form. The RNA-induced silencing complex (RISC), made up of the
mature miR-221 and several other mature miRNAs, is created by their
binding to an Argonaute (AGO) protein (\textbf{Figure 1} ) (Di Martino
et al., 2022; Markovic, Sharma, \& Balakrishnan, 2020; Visone et al.,
2007). MiR-221 contributes to the expression of specific genes,
participates in the regulation of the cell cycle, and is involved in
several biological mechanisms like cell differentiation and development
(Gao et al., 2023), immune responses (Du et al., 2018; Mikami et al.,
2021), metabolism (Y.-T. Wang, Tsai, Liao, Hsu, \& Juo, 2013), and
carcinogenesis (Guo et al., 2021), epigenetic regulators of immune cells
reprogramming (Seeley et al., 2018). Moreover, miR-221 significantly
raises the level of proinflammatory cytokines (D. Zhao, Zhuang, Ding,
Kang, \& Shi, 2016).

\textbf{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 \selectlanguage{greek}α-\selectlanguage{english}syn in PD through its
regulatory role in gene expression. miR-7 is known to bind to the 3' UTR
of the \selectlanguage{greek}α-\selectlanguage{english}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 \selectlanguage{greek}α-\selectlanguage{english}syn expression. This
reduction in miR-7 allows for increased translation of the SNCA gene and
subsequent accumulation of \selectlanguage{greek}α-\selectlanguage{english}syn protein. Therefore, the decrease in
miR-7 levels disrupts the normal regulation of \selectlanguage{greek}α-\selectlanguage{english}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.

\textbf{The neuroprotective role of miR-221 in PD: Insights from in
vitro and in vivo Studies}

miR-221 plays a crucial role in promoting neuronal survival and
protecting against oxidative stress in PD through several pathways
(\textbf{Figure 2} ). Autophagy is a process that helps maintain healthy
cells by removing damaged or nonfunctional organelles and recycling
their materials (Vargas, Hamasaki, Kawabata, Youle, \& Yoshimori, 2023).
It also destroys pathogens and removes long-lived proteins and
aggregates to maintain cell homeostasis (Kocaturk \& Gozuacik, 2018).
There are three types of autophagy observed in mammalian cells:
macroautophagy, chaperone-mediated autophagy, and microautophagy (Sato
et al., 2016). This process is important for keeping cells healthy and
has been linked to PD (Cerri \& Blandini, 2019). When autophagy is not
functioning properly, it can contribute to the development of PD (Cheung
\& Ip, 2009). Regulating autophagy is a proposed treatment strategy for
PD (Rakowski, Por\selectlanguage{polish}ę\selectlanguage{english}bski, \& Grzelak, 2022). Another process called
mitophagy, which helps remove damaged mitochondria from cells, may also
play a role in protecting brain cells in PD (Goiran, Eldeeb, Zorca, \&
Fon, 2022).

A long non-coding RNA called LncRNA-SNHG1 is significantly increased in
PD (H. Wang, Wang, Zhang, \& Zhao, 2021). It has been shown to increase
the formation of protein clumps called \selectlanguage{greek}α-\selectlanguage{english}Syn aggregates and promote
inflammation in the brain (L. Zhao \& Wang, 2019b). mTOR is an enzyme
that has a key role in controlling cellular growth, division, and
viability (Ali et al., 2022; Barzegar Behrooz et al., 2022). It is a
portion of two different protein complexes, mTORC1 and mTORC2, which
have different targets and functions within the cell (Jhanwar-Uniyal,
Dominguez, Mohan, Tobias, \& Gandhi, 2022). Signals such as growth
factors and nutrient levels activate mTORC1 which controls processes
such as protein production, cell growth, and autophagy (Movahhed et al.,
2022). mTORC2 is activated by growth factors and controls cell survival,
metabolism, and the organization of the cell's internal structure (Y.
Sun et al., 2023). When mTOR signaling is not functioning properly, it
can facilitate the development of various diseases, including cancer,
diabetes, and neurological disorders (Russo, Citraro, Constanti, \& De
Sarro, 2012; Suhara, Baba, Shimada, Higa, \& Matsui, 2017; Zou, Tao, Li,
\& Zhu, 2020). p27 is a protein that helps control cell division by
inhibiting the activity of certain enzymes called cyclin-dependent
kinases (Guiley et al., 2019). Functioning as a tumor suppressor, it
prevents uncontrolled cell proliferation and has been linked to various
types of cancer (Razavipour, Harikumar, \& Slingerland, 2020). It has
been demonstrated that p27 takes part in controlling autophagy and
apoptosis in PD (Lv, Wang, Zhong, \& Huang, 2020). LC3 II is a protein
found on the membranes of autophagosomes, which are structures involved
in autophagy (R. Wang et al., 2022). The level of LC3 II is related to
the number of autophagosomes in a cell (Kabeya et al., 2000). A study by
Qian and colleagues suggests that reducing levels of lncRNA-SNHG1 can
increase autophagy and protect against cell death in PD by affecting the
miR-221/222/p27/mTOR signaling pathway. They found that reducing
lncRNA-SNHG1 levels increased the number of autophagosomes and reduced
cell damage in a model of PD. This was due to decreased interaction
between lncRNA-SNHG1 and miR-221/222, which resulted in lower levels of
p27 and increased activity of the mTOR pathway. Blocking miR-221/222
reversed the effects of reducing lncRNA-SNHG1 levels on p27 and mTOR.
These results suggest that targeting the interaction between
lncRNA-SNHG1, miR-221/222, p27, and mTOR could be a potential treatment
strategy for PD (Qian et al., 2019).

NPTX2 is a protein concentrated in certain brain tissues and cells
affected by PD (Moran et al., 2008; Shao, Shan, Ru, \& Ma, 2020). HOTAIR
is a type of lncRNA that is associated with various diseases, including
PD, thyroid cancer, and gallbladder cancer (H.-m. Li et al., 2017; M.-z.
Ma et al., 2014; S. Wang, Zhang, Guo, Rong, \& Liu, 2017). It can affect
gene expression by interacting with proteins that modify DNA structure
and with proteins that control gene activity (Spokoini-Stern et al.,
2020). Lang and colleagues proposed that HOTAIR participated in
promoting autophagy in certain brain cells affected by PD in mice. They
found that HOTAIR levels were increased in the brains of mice with
chemically induced PD and that reducing HOTAIR levels decreased
autophagy and improved movement in these mice. They also discovered that
HOTAIR affects the levels of the NPTX2 protein by interacting with
miR-221-3p and that NPTX2 plays a role in regulating autophagy in PD.
These findings indicate that targeting the interaction between HOTAIR,
miR-221-3p, and NPTX2 could be a potential treatment strategy for PD
(Lang et al., 2020).

Crocin is a natural pigment found in saffron that gives it its bright
red color (Pan, Wen, Ma, Qin, \& Feng, 2022). It possesses antioxidant,
neuroprotective, and anti-inflammatory effects according to studies
(Kermanshahi et al., 2020; Nam et al., 2010). Research has looked at the
prospect of crocin as a treatment for various diseases, including PD,
AD, and cancer (Ahmed et al., 2020; Veisi et al., 2020). PI3K enzyme has
a crucial part in transmitting signals within cells that control cell
growth, division, differentiation, and survival (Juntilla \& Koretzky,
2008). It is activated by signals from outside the cell, such as growth
factors and hormones, and converts one type of molecule (PIP2) into
another (PIP3) (Luo, Manning, \& Cantley, 2003). PIP3 then activates
other signaling molecules within the cell, such as Akt and mTOR, which
control various cellular processes (Park et al., 2010). Akt is an enzyme
that has a crucial part in transmitting signals within cells that
control cell growth, division, differentiation, and survival (Dickson \&
Rhodes, 2004; Macintyre et al., 2011). Akt is stimulated by various
signaling components, such as growth factors, cytokines, and hormones,
and it phosphorylates downstream signaling molecules, such as mTOR,
GSK-3\selectlanguage{greek}β, \selectlanguage{english}and FoxO3a, which regulate various cellular processes (B.-G. Li,
Hasselgren, \& Fang, 2005; Salama, Abdel-Latif, Abbas, Hekmat, \&
Schaalan, 2020). A study by Rania and colleagues showed that crocin, a
natural pigment found in saffron, can protect against PD in rats exposed
to the chemical rotenone. This protective effect is achieved through the
interaction between the PI3K/Akt/mTOR signaling pathway and increased
levels of two miRNAs, miRNA-7 and miRNA-221. The PI3K/Akt/mTOR pathway
is stimulated by crocin, increasing the activity of some proteins while
reducing brain cell death. Crocin also reduces cell death and levels of
a protein called \selectlanguage{greek}α-\selectlanguage{english}syn. These results provide new information about how
crocin may protect against PD (Salama et al., 2020).

PTEN is a tumor suppressor gene that produces a protein that acts as a
phosphatase, removing phosphate groups from specific proteins
(P\selectlanguage{ngerman}érez-Ramírez, Cañadas-Garre, Molina, Faus-Dáder, \& Calleja-Hernández,
2015). It helps maintain balance in the PI3K/AKT pathway and may
suppress tumor growth independently of its role in the PI3K pathway
(Dubrovska et al., 2009). As described by the research conducted by Li
et al. miR-221 may have a protective effect in PD. Their research showed
that levels of miR-221 were substantially reduced in cell models of PD
induced by the chemical 6-OHDA. When miR-221 levels were increased, the
cells showed improved viability and growth and a decrease in cell death.
They found that AKT phosphorylation is significant in PD as it is
involved in regulating cell survival and apoptosis. miR-221 promotes AKT
phosphorylation by targeting PTEN, thereby activating the PI3K/AKT
pathway and potentially contributing to the protective role of miR-221
in PD. In summary, miR-221 can be a potential treatment goal for PD (L.
Li et al., 2018).

Apoptosis is a natural mechanism observed in multicellular organisms,
facilitating the elimination of damaged or unnecessary cells from the
body (D'arcy, 2019). This process is tightly regulated through intricate
signaling pathways and involves the activation of caspases, a class of
enzymes that act in targeted molecule degradation and subsequent
cellular breakdown (Boice \& Bouchier-Hayes, 2020). Apoptosis, or
''programmed cell death,'' is a mechanism that involves the
Bax/caspase-3 signaling pathway (Zamanian et al., 2017; Zhu et al.,
2022). BAX is a member of the Bcl-2 family of proteins, which are part
of the apoptosis regulators and either promote or inhibit cell death.
Its primary location is in the cytoplasm of cells. During apoptosis, Bax
undergoes a conformational change and translocates from the cytoplasm to
the mitochondria (Ansari, Ball, Wase, Novak, \& Haqqi, 2021). Caspase-3,
in turn, acts as a protease that selectively cleaves specific
substrates, leading to the dismantling of the cell (P. Yadav, Yadav,
Jain, \& Vaidya, 2021). Bim is a pro-apoptotic protein that participates
in controlling how cells undergo apoptosis. It belongs to the Bcl-2
family of proteins, which are essential for regulating the apoptosis of
neurons (Kim et al., 2017; Linseman et al., 2002). It has roles in the
regulation of numerous types of neurons, such as sympathetic neurons,
cerebellar granule neurons, and cortical neurons (Linseman et al.,
2002). Bim is regulated by transcriptional factors such as FOXO, Egr-1,
and the JNK/c-Jun pathway (Xie et al., 2011). About PD, the expression
of Bim is controlled by the activation of the JNK/c-jun signaling
pathway and the decrease in its translocation to the mitochondrial field
(Hu et al., 2019). According to the research, there was a notable
decrease in miR-221 levels in both the blood of PD patients and in the
brain tissue of mice with a chemically induced form of the disease. The
study showed that introducing additional miR-221 prevented the death of
dopamine-producing neurons in the mice and influenced the Bax/caspase-3
pathway by interacting with Bim, a protein that promotes cell death.
These are evidence that miR-221 could be a potential target for
developing treatments to protect dopamine-producing neurons and
alleviate symptoms of PD (Yao et al., 2023).

DJ-1 is a gene that produces a protein that helps protect cells from
oxidative stress (Kahle, Waak, \& Gasser, 2009). Changes in the DJ-1
gene have accompanied the primary development of PD (Kahle et al.,
2009). DJ-1 has been shown to regulate the thioredoxin/ASK1 complex,
which protects against oxidative damage, and to adjust miR-221 levels to
promote neuronal survival in the face of oxidative stress (Oh et al.,
2018). DJ-1 has been shown to help prevent cellular demise by protecting
against oxidative stress and it also protects nerve cells due to its
movement to the mitochondria driven by cysteine-sulfinic acid
(Canet-Avilés et al., 2004). Oh et al. discovered that DJ-1, a gene
product associated with PD, promotes neuronal preservation in the face
of oxidative stress. Their study found that when miR-221 was
overexpressed in SH-SY5Y cells, cell viability increased significantly
following treatment with MPP+, a dopaminergic neurotoxin that induces
oxidative stress. Specifically, they found that DJ-1 adjusts miR-221
levels to shield the neurons from oxidative stress. They also discovered
that when DJ-1 was knocked down, neurite outgrowth decreased and
susceptibility to cell death caused by oxidative stress increased, while
overexpression of miR-221 reduced these effects. Additionally, they
found that miR-221 targets transcripts of apoptotic proteins, including
BIM, FOXO3a, BMF, and BNIP3L, which are predicted to be suppressed by
miR-221 (Oh et al., 2018). In conclusion, DJ-1 and miR-221 could be
anticipated endpoints for the development of therapies for PD.

The SNCA gene is associated with PD and produces a protein called \selectlanguage{greek}α-\selectlanguage{english}syn.
Changes in the SNCA gene have been associated with inherited types of
PD. (Deng \& Yuan, 2014). This protein is a key constituent of the
protein aggregates known as Lewy bodies, which are present in the brains
of individuals with PD (Fields, Bengoa-Vergniory, \& Wade-Martins,
2019). The PARK2 gene is also associated with PD and produces a protein
called parkin. Changes in the PARK2 gene have been associated with
early-onset forms of PD (Nuytemans, Theuns, Cruts, \& Van Broeckhoven,
2010). Parkin helps break down damaged or misfolded proteins in cells
(Kilarski et al., 2012). When parkin doesn't function properly, toxic
proteins can build up in cells which can lead to the development of PD
(Kilarski et al., 2012). Tatura et al. reported that miR-221 is
upregulated in their study and its upregulation is consistent with the
observed decrease in SNCA transcript levels. Additionally, the
downregulation of miR-221 is consistent with its potential role in the
onset and development of PD (Tatura et al., 2016).

TfR2, or transferrin receptor 2, is a protein that helps regulate the
balance of iron in the body (Piperno et al., 2004). It acts as a carrier
for transferrin, a molecule that binds to iron and transports it to
different parts of the body (Robb \& Wessling-Resnick, 2004). TfR2
shares some similarities with another transferrin receptor protein
called TfR1, but its specific function in iron regulation is not yet
fully understood (Kleven, Jue, \& Enns, 2018). TfR2 is present in
various tissues, like the liver as well as pancreas, and brain, and
mutations in the TfR2 gene have been detected in a rare genetic disorder
called hereditary hemochromatosis type 3, which is characterized by iron
overload in the body (Bao et al., 2016; Yamamoto et al., 2002). Asci et
al. used various techniques, including bioinformatics tools and miRNA
inhibitors, to identify and manipulate miRNAs that may be involved in
regulating TfR2 expression. They found that inhibiting endogenous levels
of miR-221 in SH-SY5Y cells increases the expression of TfR2, and both
the mRNA and protein expression of TfR2 can be reduced by miR-221. The
research also showed that microRNA 221 interacts with a specific part of
the TfR2 messenger RNA molecule and reduces its activity. This suggests
that miR-221 can decrease the production of TfR2 protein. In conclusion,
miR-221 may help adjust TfR2 levels in certain cells and could provide
insight into the development of PD (Asci et al., 2013).

Paraoxonase 1 (PON1) is an enzyme that helps protect against oxidative
stress (Kotur-Stevuljevic et al., 2015). PD is characterized by a
disproportion between acetylcholine (ACh) and dopamine (DA) in the CNS
(Rizzi \& Tan, 2017). This is mainly due to the degeneration of
dopaminergic neurons in the substantia nigra (Leh\selectlanguage{ngerman}éricy, Sharman, Santos,
Paquin, \& Gallea, 2012). Acetylcholinesterase can be attacked and
inhibited by free radicals such as peroxide and organophosphate
substances, which causes an increase in acetylcholine and worsens the
imbalance between ACh and DA (Al-Baggou, Naser, \& Mohammad, 2011;
Pearson \& Patel, 2016). To block the imbalance between ACh and DA, the
PON1 enzyme suppresses these free radicals (Menini \& Gugliucci, 2014).
Arylesterase, (ARE) is an enzyme that is involved in the metabolism of
organophosphate compounds (Piras et al., 2021). According to a report by
Ghita and Deeb, serum levels of miRNAs (miR-214, miR-141, and miR-221)
and antioxidants (uric acid, PON1, and ARE) were significantly lower in
cases with PD in comparison to healthy individuals (Ghit \& Deeb, 2022).
UPDRS-III is utilized to evaluate the movement-related symptoms of PD,
including shaking, stiffness, slowed movement, and balance issues (M. Lu
et al., 2020). The scale has a range of 0 to 108, where a higher score
signifies more severe motor symptoms (Thobois et al., 2002). UPDRS-V is
utilized to evaluate the daily living activities and independence of
individuals with PD (Shu, Qian, \& Wang, 2020). The scale has a range of
0 to 100, where a higher score signifies greater dependence on others
for performing daily activities (Tibar et al., 2018).

The Area Under the Curve (AUC) value ranges from 0 to 1, with 0.5
indicating a test with no discriminatory ability (equivalent to random
chance) and 1 indicating a perfect test that can accurately distinguish
between the two groups (Walter, 2005; Wolever, 2004). Ma et al.
discovered that serum miR-221 was considerably reduced in individuals
with PD and had a positive correlation with UPDRS-III and UPDRS-V
scores, showing its potential as an indicator of PD severity. The AUC
value for predicting PD using serum miR-221 was 0.787, suggestive of its
prospective use as a biomarker for diagnosing PD. These findings suggest
that downregulated serum miR-221 might be considered a biomarker for the
assessment of PD (W. Ma et al., 2016).



\textbf{Conclusion}

PD is a neurodegenerative condition that mainly impacts the motor
system. Dopamine-producing cells in the substantia nigra gradually start
to disappear in this condition. Small non-coding RNA molecules known as
miRNAs are essential in the control of gene expression. Studies have
demonstrated that miRNAs play a role in the development of PD. In
particular, several studies have investigated the potential of serum
miRNAs as biomarkers for PD. miR-221 has been suggested to play a role
in the pathogenesis of PD. Several studies have investigated the
function of miR-221 in PD. For example, one study identified miR-221 as
a promising non-invasive biomarker for PD, with a moderate to good
predictive power for the disease. These findings suggest that miR-221
plays a crucial role in promoting neuronal survival and protecting
against oxidative stress in PD. Therefore, targeting miR-221 may
represent a potential intervention strategy for PD patients. By
increasing the expression of miR-221, it may be possible to enhance
neuronal survival and protect against oxidative stress, which are key
factors in the pathogenesis of PD. However, further research is needed
to fully understand the therapeutic potential of targeting miR-221 in
PD.

\textbf{Ethical Approval}

Not applicable



\textbf{Authors' contributions}

R.G, K.P, \& H.O.A; investigation, B.M.H, H.A \& M.F.R; resources,
M.Y.Z., T.O. \& M.S.I.; data curation, M.S.I., T.O \& M.Y.Z.;
writing---original draft preparation, M.G., N.N \& M.Y.Z.;
writing---review and editing, M.G. \& M.K visualization and supervision,
M.G. \& M.K; project administration. All authors have read and agreed to
the published version of the manuscript.

\textbf{Funding}

This research received no external funding.

\textbf{Availability of data and materials}

Not applicable.

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