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.