This review was conducted by searching PubMed, Scopus, and Google Scholar databases using the keywords “Parkinson’s disease,” “α-synuclein,” “dopaminergic neurons,” “LRRK2,” “mitochondrial dysfunction,” “comorbidities,” “levodopa,” and “neuroinflammation.” Studies published in English between 2000 and 2025 were included. Preference was given to peer-reviewed original research, clinical trials, and systematic reviews. Articles were excluded if they lacked relevance to neurobiological or clinical aspects of Parkinson’s disease. A total of 216 sources were shortlisted, of which 120 were cited based on scientific quality and thematic relevance.

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder globally, surpassed only by Alzheimer’s disease (Zaguirre, 2023). Affecting more than 10 million people worldwide, its incidence is expected to double by 2040 due to population aging and improved survival rates (WHO, 2020; Zhong and Zhu, 2022). PD is clinically characterized by a triad of motor symptoms—bradykinesia, rigidity, and resting tremor—alongside a range of debilitating nonmotor symptoms such as depression, anxiety, cognitive decline, and autonomic dysfunction (Panicker et al., 2021; Hindle et al., 2018).

Parkinson’s disease (PD) poses an escalating global health challenge, with recent WHO data projecting a near doubling in cases by 2040 (WHO, 2020; Zhong and Zhu, 2022). The global societal burden is equally significant, with total direct and indirect costs estimated to exceed $112 billion USD annually by 2023 (Ola et al., 2022; Chaudhuri et al., 2024). Beyond the clinical manifestations, PD incurs heavy economic costs due to prolonged caregiving, disability, and lost productivity. High-income countries (HICs) typically provide structured care and insurance-based support, while low- and middle-income countries (LMICs) face limited access to neurologists, diagnostic tools, and long-term care facilities (Payami et al., 2023; Masoom et al., 2018). These global disparities necessitate region-specific policy planning, emphasizing both infrastructure and research capacity-building in under-resourced regions (Payami et al., 2023; Masoom et al., 2018).

Originally described in 1817 by James Parkinson as a purely motor disorder (Parkinson, 1817), PD is now recognized as a complex, multisystem disease involving a confluence of molecular, genetic, environmental, and immunological factors (Rode Karan Ganesh et al., 2024; Franco et al., 2021). Mutations in genes such as SNCA, LRRK2, PARK7, PINK1, and VPS35 are associated with familial forms of PD, while pesticide exposure, heavy metals, and industrial chemicals contribute to sporadic cases. Additionally, early nonmotor symptoms—such as anosmia, REM sleep behavior disorder (RBD), and gastrointestinal dysfunction—are increasingly identified as prodromal indicators.

PD poses a substantial economic burden globally. In the United States alone, the annual cost of PD exceeds $52 billion, including direct medical expenses and indirect costs such as lost productivity and caregiver burden (Ola et al., 2022; Chaudhuri et al., 2024). This burden is disproportionately heavier in low- and middle-income countries (LMICs), where underdiagnosis, limited therapeutic access, and healthcare disparities amplify disease impact (Payami et al., 2023; Masoom et al., 2018).

This review synthesizes contemporary insights into PD’s pathophysiology, genetic and environmental risk factors, comorbidities, and therapeutic innovations. Particular emphasis is placed on emerging tools such as stem cell therapy, CRISPR-Cas9 editing, AI-assisted diagnostics, and nanocarrier-mediated drug delivery. We also explore the role of global collaboration and policy strategies to address PD’s escalating prevalence and unmet clinical needs, especially in resource-limited settings.

Recent findings support the hypothesis that α-synuclein pathology originates in the enteric nervous system and ascends to the brain via the vagus nerve. This aligns with the “body-first” PD subtype theory, suggesting that peripheral initiation may precede CNS involvement (Goedert et al., 2017; Wu et al., 2023). Moreover, exosomal transfer and templated seeding of misfolded α-synuclein contribute to its prion-like behavior (Dorsey et al., 2024). Lewy bodies, once thought to be mere markers, are now considered active participants in disease propagation due to their interaction with endolysosomal and mitochondrial pathways (Dorsey et al., 2024; Murphy and McKernan, 2022).

The misfolding and aggregation of α-synuclein into insoluble fibrils is a pathological hallmark of PD. These aggregates accumulate in neuronal cytoplasmic inclusions known as Lewy bodies and Lewy neurites (Goedert et al., 2017; Wu et al., 2023). Recent research supports a prion-like propagation model, where pathogenic α-synuclein spreads trans-neuronally via exosomes and synaptic transmission, initiating a chain reaction of misfolding across interconnected brain regions. This contributes to the progression from prodromal to symptomatic PD stages (Dorsey et al., 2024; Murphy and McKernan, 2022).

α-Synuclein interferes with synaptic vesicle trafficking, mitochondrial dynamics, and axonal transport, ultimately leading to synaptic dysfunction, impaired neurotransmission, and axonopathy. Post-translational modifications such as phosphorylation at Ser129 further enhance its aggregation propensity and neurotoxicity (Goedert et al., 2017; Wu et al., 2023).

In addition to complex I deficiency, dysfunction of mitochondrial quality control pathways—specifically PINK1/Parkin-mediated mitophagy—plays a pivotal role. Under physiological conditions, PINK1 accumulates on depolarized mitochondria and recruits Parkin to facilitate their degradation. Mutations in either gene impair this surveillance, allowing damaged mitochondria to persist and propagate oxidative stress (Franco et al., 2021; Luo et al., 2022). Furthermore, DJ-1, a redox-sensitive protein, is involved in protecting neurons from oxidative damage and modulating mitochondrial integrity, linking environmental and genetic risk (Franco et al., 2021; Luo et al., 2022).

Mitochondrial complex I deficiency is consistently observed in PD, leading to impaired ATP synthesis and overproduction of reactive oxygen species (ROS) (Chang and Chen, 2020; Zeng et al., 2024). Accumulated ROS cause oxidative damage to lipids, DNA, and proteins, creating a pro-degenerative cellular environment (Chang and Chen, 2020; Zeng et al., 2024). Genetic mutations in PINK1 and PARKIN, which regulate mitophagy, impair the clearance of damaged mitochondria, exacerbating oxidative stress (Franco et al., 2021; Luo et al., 2022).

Furthermore, LRRK2 mutations—particularly G2019S—are linked to disrupted mitochondrial dynamics, altered kinase activity, and aberrant autophagy (Franco et al., 2021; Luo et al., 2022). VPS35, a component of the retromer complex, contributes to mitochondrial fragmentation and impaired trafficking, particularly affecting dopaminergic neurons (Franco et al., 2021; Luo et al., 2022).

Ferroptosis is an emerging mechanism in PD, characterized by iron-dependent lipid peroxidation. Postmortem analyses reveal excessive iron accumulation in the SNpc, correlating with dopaminergic neuron loss (Wang et al., 2023; Xing et al., 2023). Iron promotes Fenton chemistry, enhancing hydroxyl radical production and driving oxidative injury (Wang et al., 2023; Xing et al., 2023). Key regulators such as glutathione peroxidase 4 (GPX4), ferritin, and transferrin are dysregulated in PD, suggesting therapeutic potential for ferroptosis inhibitors and iron chelators (Wang et al., 2023; Xing et al., 2023).

Studies show that α-synuclein may bind iron directly, promoting its aggregation, while lipid peroxidation products further stabilize toxic oligomers (Wang et al., 2023; Xing et al., 2023).

Chronic neuroinflammation is another driver of PD progression. Activated microglia and astrocytes release proinflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), creating a hostile neuroimmune milieu (Isik et al., 2023; Eidson et al., 2017; Fu et al., 2023). These cytokines disrupt blood–brain barrier integrity, potentiate oxidative stress, and induce apoptotic signaling pathways (Isik et al., 2023; Eidson et al., 2017; Fu et al., 2023).

In PD brains, persistent glial activation is associated with regions of dopaminergic degeneration, indicating a spatial correlation (Isik et al., 2023; Eidson et al., 2017; Fu et al., 2023). In addition, peripheral inflammation—linked to comorbid conditions like diabetes and HIV—may exacerbate central neuroinflammatory responses (Isik et al., 2023; Eidson et al., 2017; Fu et al., 2023).

Epigenetic regulation also influences proteostasis in PD. Alterations in histone acetylation and DNA methylation affect the transcription of key autophagy genes such as ATG5 and LC3B. MicroRNAs (miRNAs) like miR-34b/c and miR-7 have been implicated in regulating α-synuclein expression and lysosomal biogenesis. These findings suggest that targeting epigenetic modifiers and miRNA networks may offer novel therapeutic opportunities (Isik et al., 2023; Eidson et al., 2017; Fu et al., 2023).

The autophagy-lysosomal pathway (ALP) and ubiquitin-proteasome system (UPS) are critical for degrading misfolded proteins. In PD, mutations in GBA, ATP13A2, and PARK9 impair lysosomal function, leading to α-synuclein accumulation and cellular toxicity (Behl et al., 2022; Luo et al., 2022). Dysregulated mTOR signaling and defective chaperone-mediated autophagy further inhibit proteostasis (Behl et al., 2022; Luo et al., 2022).

In particular, LRRK2 mutations impair endolysosomal trafficking, contributing to α-synuclein clearance failure and promoting neurodegeneration (Behl et al., 2022; Luo et al., 2022).

PD predominantly affects individuals over the age of 60, with incidence rising sharply after the age of 70. Epidemiological analyses reveal a male predominance, with men exhibiting approximately 1.5 times higher risk than women (Ben-Shlomo et al., 2024). This disparity is hypothesized to arise from differences in estrogen-mediated neuroprotection, lifestyle factors, and occupational exposure to neurotoxins (Ben-Shlomo et al., 2024) (Figure 2).

The prevalence and incidence of PD vary across countries and regions, influenced by demographic structure, industrialization, access to healthcare, and awareness levels. High-income countries (HICs) report higher prevalence rates due to better diagnostic tools, registry systems, and longer life expectancy. However, low- and middle-income countries (LMICs) are experiencing the steepest rise in new PD cases, largely due to demographic transition and under-recognition in the past (Masoom et al., 2018; Rahman et al., 2025) (Figure 3).

PD imposes a significant socioeconomic burden, including direct healthcare costs (e.g., medications, hospitalizations, and surgery) and indirect costs (e.g., lost income, caregiver absenteeism, and reduced productivity). In the United States alone, the economic burden of PD exceeded $52 billion in 2020, with caregivers losing an average of $19,000 in annual income due to reduced work hours or job loss (Chaudhuri et al., 2024).

Comparative studies show that while HICs absorb higher per-patient costs through insurance systems and assistive infrastructure, LMICs face a disproportionately higher household-level burden, where out-of-pocket expenses can consume over 50% of monthly income (Ola et al., 2022) (Figures 4, 5).

A significant proportion of PD patients in LMICs remain undiagnosed or misdiagnosed, especially in rural and low-resource settings. Contributing factors include:

Lack of trained neurologists or movement disorder clinics.

Establishing national PD registries, integrating PD into noncommunicable disease (NCD) strategies, and investing in mobile health screening tools are critical steps toward improved surveillance and resource allocation. (Gupta and Dhawan, 2021).

Over 40–60% of PD patients experience depression and anxiety, which are often underdiagnosed and misattributed to motor disability (Lee et al., 2022; Elefante et al., 2021). These symptoms are linked to degeneration in serotonergic and noradrenergic circuits, particularly in the raphe nuclei and locus coeruleus, and may manifest years before classical motor signs (Lee et al., 2022; Elefante et al., 2021).

Cognitive impairment, ranging from mild cognitive dysfunction to Parkinson’s disease dementia (PDD), affects up to 80% of individuals in advanced stages (25). This is attributed to Lewy body pathology in cortical regions, cholinergic depletion, and altered frontostriatal connectivity. Psychiatric symptoms may also be exacerbated by dopamine replacement therapy (DRT), particularly dopamine agonists, which can trigger impulse control disorders, hallucinations, and psychosis (Burchill et al., 2024; Taslim et al., 2024).

Diagnostic challenge: Differentiating neuropsychiatric manifestations from motor-induced cognitive slowness or medication side effects requires multidisciplinary assessment. Use of validated scales (e.g., MoCA, GDS, HADS) in routine care is recommended.

Autonomic dysfunction is a hallmark nonmotor feature of PD and includes:

Orthostatic hypotension (in up to 30–40%).

Cardiac sympathetic denervation, detectable via ¹²³I-MIBG scintigraphy, is strongly associated with disease progression (Grosu et al., 2023). These cardiovascular abnormalities increase fall risk, exacerbate fatigue, and limit the use of medications such as anticholinergics and MAO-B inhibitors (Grosu et al., 2023).

Management complications: Cardiovascular symptoms complicate pharmacotherapy by interacting with anti-parkinsonian drugs that modulate autonomic tone, requiring dose balancing and often necessitating cardiology consultation (Sharkey and Modarai, 2018; Al-Kuraishy et al., 2023).

HIV-positive individuals are at increased risk of parkinsonism due to basal ganglia vulnerability to viral neurotoxicity, chronic inflammation, and mitochondrial stress (Denaro et al., 2022; Hassan et al., 2020). HIV-associated neurocognitive disorders (HAND) share overlapping features with PD, including bradykinesia and cognitive dysfunction (Denaro et al., 2022; Hassan et al., 2020).

Moreover, antiretroviral therapy (ART), particularly protease inhibitors and nucleoside reverse transcriptase inhibitors, can:

Interfere with dopamine metabolism.

Thus, HIV–PD co-management requires careful drug selection and neurology–infectious disease collaboration to avoid worsening symptoms or drug–drug interactions.

T2DM is a significant comorbidity in PD, with shared pathogenic features including:

Insulin resistance in the CNS.

Epidemiological studies suggest a 30–50% increased risk of PD in patients with T2DM (Hassan et al., 2020; Camargo et al., 2019). T2DM may also accelerate PD progression, worsen cognitive decline, and impair motor response to Levodopa. Conversely, certain GLP-1 receptor agonists, such as exenatide, have shown neuroprotective effects in clinical trials, indicating the potential for cross-therapeutic benefits (Troshneva and Ametov, 2022).

Emerging evidence highlights the role of gut microbiota in PD pathophysiology. PD patients frequently exhibit dysbiosis, characterized by:

Reduced short-chain fatty acid–producing bacteria (e.g., Faecalibacterium).

Gut inflammation and barrier dysfunction may facilitate α-synuclein misfolding in the enteric nervous system, with retrograde propagation via the vagus nerve (Li et al., 2023; Turco et al., 2023). Animal models support this bottom-up mechanism of disease initiation (Li et al., 2023; Turco et al., 2023).

Probiotics, prebiotics, and synbiotics are under clinical investigation as adjunct therapies to modulate gut-brain interactions and reduce systemic inflammation (Chan et al., 2022; Hashish and Salama, 2023).

Levodopa, often co-administered with carbidopa to inhibit peripheral metabolism, is the gold standard for PD treatment. However, chronic use is associated with:

Motor fluctuations (wearing-off, on–off phenomena).

To enhance efficacy and reduce complications, combination therapies employ:

MAO-B inhibitors (e.g., rasagiline).

Yet these agents often exacerbate neuropsychiatric and cardiovascular side effects, especially in older patients, limiting their use (Suárez Castro et al., 2016; Khan et al., 2023).

DBS is indicated in patients with severe motor fluctuations and Levodopa-induced dyskinesia. It involves stereotactic implantation of electrodes into deep brain structures, most commonly:

Subthalamic nucleus (STN).

Efficacy comparison:

DBS significantly improves motor function and quality of life, particularly in patients with advanced disease and medication-refractory symptoms (Hacker et al., 2020; Rawls, 2022; Hitti et al., 2019; Rahimpour et al., 2022). Compared to pharmacological treatment, DBS provides sustained symptom control and reduces Levodopa requirements. However, risks include surgical complications, hemorrhage, infection, and neuropsychiatric side effects, necessitating careful patient selection and multidisciplinary evaluation (Cury et al., 2022; Wagle Shukla et al., 2017) (Table 1).

The BBB severely restricts CNS penetration of most therapeutic agents. Emerging nanocarrier platforms aim to improve drug bioavailability and target specificity (Naqvi et al., 2020; Inamdar et al., 2024):

Liposomes: biocompatible vesicles for encapsulating Levodopa and neuroprotective agents.

These carriers can be engineered for surface modification with ligands targeting dopaminergic neurons or inflamed brain regions, enabling precision delivery and minimizing off-target toxicity (Naqvi et al., 2020; Inamdar et al., 2024).

Gene therapy in PD aims to:

Restore dopamine synthesis: e.g., via delivery of aromatic L-amino acid decarboxylase (AADC).

AAV2-based vectors have been used in clinical trials to deliver therapeutic genes to the striatum or SNpc, showing safety and moderate benefit (Niethammer et al., 2017; Sen et al., 2025). However, challenges remain in target specificity, long-term expression, and immune response (Inoue et al., 2023; Sharma et al., 2025).

Stem cell therapies offer the potential to replace lost dopaminergic neurons and restore neural circuitry. Promising cell types include:

Induced pluripotent stem cells (iPSCs): Autologous and genetically matched.

Preclinical models and early-phase trials have shown motor improvement and graft survival, but issues such as immune rejection, tumorigenicity, and ethical concerns need resolution (Xiao and Tan, 2023; Li et al., 2023; Cha et al., 2023; Barker, 2019).

CRISPR-Cas9 enables precise genome editing and holds transformative potential for monogenic PD, particularly:

Correction of LRRK2 G2019S, SNCA triplications, or PINK1 mutations.

Currently, CRISPR is limited to in vitro and animal studies due to safety and ethical barriers, but advances in delivery vectors and base editing technologies may accelerate clinical translation (Inoue et al., 2023; Sharma et al., 2025).

AI and machine learning (ML) are revolutionizing PD management through:

Early diagnosis: analyzing digital biomarkers (e.g., voice, gait, handwriting).

Wearable sensors and smartphones now enable real-time symptom tracking, and ML algorithms can stratify patients for adaptive trial designs and biomarker discovery (Burchill et al., 2024; Taslim et al., 2024) (Figure 6).

Biomarkers are essential for diagnosing PD in its prodromal phase, tracking progression, and predicting treatment response. Promising classes include:

Protein biomarkers: α-synuclein (total and phosphorylated), neurofilament light chain (NfL), DJ-1.

Longitudinal cohort initiatives like the Parkinson’s Progression Markers Initiative (PPMI) and BioFIND are accelerating multi-omic biomarker integration. However, most candidates require standardization across labs, ethnic groups, and disease stages before clinical deployment.

Traditional PD trials are constrained by:

Slow progression of disease markers.

Future trials should adopt:

Adaptive designs: allow protocol adjustments based on interim data.

Moreover, digital endpoints (e.g., gait variability, voice modulation, tremor amplitude) using AI analytics offer objective and continuous monitoring over traditional scales like the Unified Parkinson’s Disease Rating Scale (UPDRS).

The heterogeneity of PD underscores the need for personalized therapy. Key enablers include:

Genetic profiling: stratifying patients by mutations (LRRK2, GBA, PINK1) to match targeted treatments.

Precision medicine is already guiding trials for LRRK2 inhibitors, GCase modulators, and GLP-1 analogues, representing a shift toward therapies tailored to molecular etiology and patient-specific risk profiles.

Most PD research and trials are concentrated in high-income countries, neglecting ethnic diversity, LMIC-specific risk factors, and accessibility challenges. Priorities include:

Building local research capacity: training neurologists and establishing centers of excellence in LMICs.

Public-private partnerships and South–South collaborations are essential to ensure global equity in PD care and innovation.

See Table 2.

Pathogenesis: PD is driven by interlinked mechanisms including α-synuclein aggregation, mitochondrial dysfunction, ferroptosis, and neuroinflammation.

See Table 3.

Expand early screening and AI-based diagnostic tools in primary and rural care settings to detect PD in prodromal stages.

The future of PD care must be multidimensional, digitally enabled, and globally inclusive. Investments in biomarker discovery, personalized therapies, and innovative trial frameworks should be matched by equitable health system reforms and coordinated policy alignment. Only through interdisciplinary collaboration, open science, and technology-driven democratization of care can the field transition from symptomatic palliation to genuine disease modification (Table 4).