Parkinson’s disease

PD is a progressive neurodegenerative disorder and is widely recognized as the second most common neurodegenerative disease after AD. PD affects millions of individuals globally and poses a significant burden on patients, caregivers, and healthcare systems due to its chronic and progressive nature. The pathological hallmark of PD is the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in a marked reduction in striatal dopamine levels and impaired basal ganglia circuitry. Dopamine deficiency underlies the characteristic motor dysfunctions of the disease and contributes to numerous non‑motor manifestations [44].

Clinically, PD is characterized by cardinal motor symptoms including bradykinesia (slowness of movement), resting tremor, rigidity, and postural instability, which progressively worsen with disease advancement. In addition to motor dysfunction, PD patients frequently experience a spectrum of non‑motor symptoms, such as cognitive impairment, mood disorders (e.g. depression, anxiety), autonomic dysfunction (e.g. orthostatic hypotension), sleep disturbances (e.g. REM sleep behaviour disorder), and olfactory deficits, often appearing in prodromal or early stages of the disease. These non‑motor features substantially impact quality of life and may precede motor signs by years [45].

PD is neuropathologically defined by two principal hallmarks: the selective loss of dopaminergic neurons in the SNpc and the presence of Lewy bodies (LBs). LBs are neuronal inclusions that develop intracellularly and are primarily composed of misfolded and aggregated α‑synuclein, reflecting a core pathological feature of PD and related synucleinopathies [46].

α‑synuclein is a 140-amino acid presynaptic protein encoded by the SNCA gene. Under physiological conditions, α‑synuclein exists predominantly as a soluble, intrinsically disordered monomer in the cytosol, but it can adopt α‑helical conformations upon association with synaptic vesicles and lipid membranes. In this state, it plays important roles in synaptic vesicle dynamics, including modulation of vesicle mobility, clustering, and the assembly of presynaptic machinery essential for efficient neurotransmitter release and synaptic homeostasis [46-48].

In healthy neurons, α‑synuclein contributes to presynaptic regulation by interacting with vesicle‑associated proteins such as VAMP2 and components of the SNARE complex, facilitating vesicle docking and neurotransmitter exocytosis. Its conformational flexibility enables dynamic engagement with membranes and protein partners critical for maintaining synaptic function and dopaminergic signalling [47].

In humans, α-synuclein is a member of the synuclein protein family, which also includes β-synuclein and γ-synuclein. Although β- and γ-synucleins share considerable structural similarity with α-synuclein, only α-synuclein exhibits a strong propensity for pathological aggregation, a defining feature of PD and related synucleinopathies. The aggregation behaviour and cytotoxicity of α-synuclein are critically regulated by PTMs, including phosphorylation, ubiquitination, nitration, sumoylation, and C-terminal truncation. Among these, phosphorylation at Ser129 is the most abundant modification detected in LBs and is strongly associated with pathological aggregation and neurotoxicity. In contrast, tyrosine phosphorylation at Tyr125, Tyr133, and Tyr136 has been reported to modulate α-synuclein aggregation dynamics and may contribute to neuroprotective signalling pathways [49,50].

α-synuclein undergoes a stepwise misfolding and aggregation process, progressing from monomeric forms to higher-order assemblies. Under pathological conditions, monomeric α-synuclein self-assembles into soluble oligomers, which can range from small dimers and trimers to larger multimeric species, before elongating into protofibrils and eventually forming insoluble mature fibrils that constitute the core of LBs. Soluble oligomeric intermediates are widely considered the most neurotoxic species in the aggregation continuum, as they disrupt multiple cellular processes. These toxic oligomers interfere with synaptic vesicle trafficking, impair dopamine release, disrupt calcium homeostasis, and induce oxidative stress, all of which contribute to mitochondrial dysfunction and neuronal injury, thus playing a critical role in PD pathogenesis [51,52].

Structurally, α-synuclein is composed of three distinct domains: The N-terminal amphipathic region (residues 1-60), which mediates membrane binding and α-helix formation; the non- Aβ component (NAC) domain (residues 61-95), which is hydrophobic and crucial for β-sheet stacking and aggregation into fibrils; and the C-terminal acidic region (residues 96-140), which regulates chaperone interactions, PTMs, and aggregation propensity. The NAC domain drives fibrillization due to its hydrophobic character, whereas the acidic C-terminal region modulates α-synuclein’s interactions with metal ions, kinases, phosphatases, and molecular chaperones, thereby influencing both physiological function and pathological aggregation [53,54].

Mitochondrial dysfunction is a central feature of PD pathogenesis. Impairment of mitochondrial complex I activity, particularly in the substantia SNpc, leads to reduced ATP production, increased generation of reactive oxygen species (ROS), and oxidative damage to lipids, proteins, and DNA. These mitochondrial deficits promote α-synuclein aggregation and exacerbate dopaminergic neuronal death. Additionally, α-synuclein interacts with mitochondria-associated membranes, modulating calcium buffering, mitochondrial dynamics (fission and fusion), and mitophagy. Mutations in PINK1 (PTEN-induced kinase 1) and Parkin impair mitophagy, resulting in the accumulation of dysfunctional mitochondria and increased vulnerability to oxidative stress. Similarly, DJ-1 mutations compromise antioxidant defences, further heightening neuronal susceptibility to degeneration [55,56].

Multiple kinase pathways regulate α-synuclein phosphorylation and influence PD progression. Key kinases, including GSK3β, casein kinase 1 and 2 (CK1/CK2), polo-like kinase 2 (PLK2), and leucine-rich repeat kinase 2 (LRRK2), have been identified as major modulators of Ser129 phosphorylation. Hyperactivation of these kinases is associated with enhanced α-synuclein aggregation, impaired synaptic function, and increased neuronal death. In contrast, phosphatases such as PP2A and PP2B counteract phosphorylation, underscoring the importance of dynamic kinase-phosphatase regulation in maintaining neuronal homeostasis and modulating PD pathology [57].

The ubiquitin-proteasome system and the autophagy-lysosomal pathway are critical for α-synuclein clearance. Impairment of proteasomal degradation or lysosomal dysfunction results in cytoplasmic accumulation of α-synuclein, formation of oligomers and fibrils, and subsequent neuronal toxicity. Chaperone-mediated autophagy selectively degrades monomeric α-synuclein via LAMP2A, while macroautophagy facilitates the removal of aggregated species. Mutations in GBA1, which encodes glucocerebrosidase, compromise lysosomal function and exacerbate α-synuclein accumulation, linking lysosomal dysfunction directly to PD pathogenesis [58,59].

LBs, the pathological hallmark of PD, follow Braak staging in their distribution. α-Synuclein accumulation initially occurs in the olfactory bulb and lower brainstem, corresponding to prodromal symptoms such as hyposmia and constipation. This is followed by involvement of the midbrain, leading to motor symptoms including bradykinesia and rigidity, and eventually spreads to cortical regions, contributing to cognitive decline and dementia. Structurally, LBs are composed of a dense core of fibrillar α-synuclein, surrounded by membranous organelles, vesicles, and ubiquitinated proteins, reflecting impaired protein homeostasis and cellular stress responses [60].

α-Synuclein also performs essential physiological functions, including regulation of synaptic vesicle pools, dopamine synthesis, vesicle recycling, synaptic plasticity, and protection against oxidative stress. Disruption of these functions-whether due to misfolding, PTMs, or impaired clearance-contributes to the neurodegenerative cascade in Parkinson’s disease. The interplay between mitochondrial dysfunction, oxidative stress, α-synuclein aggregation, kinase signalling, and impaired protein degradation forms a complex pathogenic network that drives progressive dopaminergic neuronal loss [61].