Mutations of seven genes have been definitely linked to PD, and these are PARK1/4 (SNCA, encoding α-synuclein), PARK2 (PRKN, encoding parkin), PARK7/DJ-1 (encoding parkinsonism associated deglycase), PINK1 (encoding phosphatase and tensin homolog (PTEN)-induced kinase 1), LRRK2 (encoding leucine-rich repeat kinase 2), VPS35 (encoding vacuolar protein sorting ortholog 35, involved in autophagy), and GBA1 (GTP-binding protein type A1, encoding lysosomal β-glucocerebrosidase 1) [20,21,22,23,24,25,26]. Mutations in three genes, PARK1/4 (SNCA), LRRK2 and VPS35, are known to cause a dominant form of PD, whereas mutations in PARK2 (PRKN), PINK1, and PARK7 cause recessive-inherited forms of the disease [27]. Mutations in GBA1 are causal for the rare autosomal storage disorder Gaucher disease, and they are genetic risk factors for the development of Parkinson’s disease and related synucleinopathies. A least 495 different mutations, found throughout the 11 exons of the gene are reported, which may lead to the degradation of the protein, disruptions in lysosomal targeting and diminished performance of the enzyme in the lysosome  [26]. As for those indefinitely linked to PD, more than 100 genes or genetic loci have been identified, and most cases likely arise from interactions among many common and rare genetic variants [28]. 

It is believed that most cases (85–90%) of PD are sporadic, which are characterized by signs and symptoms of progressive motor and non-motor dysfunctions [29]. The sporadic forms of PD are associated with various aggressive environmental factors, including the effects of neurotoxins (e.g., 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP), pesticides and herbicides, such as rotenone and paraquat [30,31,32], as well as factors, such as aging, traumatic brain injury, vascular risk factors, hypertension, diabetes mellitus, obesity and metabolic syndrome, depression, drugs addiction, physical inactivity, smoking, and alcohol consumption [33,34,35,36]. Such impacts lead to the ROS formation, and oxidative stress. These processes are most intensive in dopaminergic neurons of SN, which eventually die and no longer control the striatal neurons that maintain muscle tone.

The molecular pathogenesis of sporadic forms includes not only oxidative stress, but also many other pathways and mechanisms: mitochondrial dysfunction, αSyn proteostasis, calcium homeostasis, axonal transport, and neuroinflammation. Mitochondrial dysfunction plays a fundamental and complex role in many neurodegenerative disorders, including PD [37]. PD-associated mitochondrial dysfunction can result from impairment of mitochondrial biogenesis, increased ROS production, defective mitophagy, compromised trafficking, electron transport chain (ETC) dysfunction (Figure 1), variations to mitochondrial dynamics, calcium imbalance and possibly other indirect influences on mitochondrial function from unrelated pathways [38,39]. 

The involvement of MCh in the pathogenesis of PD was first identified following human consumption of illicit drugs contaminated with MPTP [40], which is oxidized by monoamine oxidase B (MAO-B) to its toxic bioactive form MPP+ entering DA-producing neurons in the SN via the DA reuptake system [41]. MPP+ inhibits the mitochondrial NADH-ubiquinone oxidoreductase of the ETC Complex I (Figure 1) and leads to electron leakage and the formation of ROS in MCh [42].

Braak and colleagues postulated a hypothesis that microbial pathogens (viruses or bacteria) in the gut could be responsible for the initiation of sporadic PD [43]. Several years later, the same scientific team suggested the dual-hit hypothesis, according to which sporadic PD starts in two places: the neurons of the nasal cavity and the neurons in the gut, spreading via the olfactory tract and the vagal nerve, respectively, toward and within the central nervous system (CNS) [44,45]. Braak’s hypothesis is supported by in vitro, in vivo, and clinical evidence [46]. 

Most cases of sporadic PD are characterized by abnormal accumulation and aggregation of αSyn within neuronal cells in the nigrostriatum, which is converted into amyloid fibrils and deposited in LB. Post-mortem brain studies of people ranging from early stages of PD to advanced stages show that LB first appears in the olfactory bulb, the gut nervous system, and the dorsal motor nucleus of the vagus located in the medulla oblongata [47,48]. LB then appears in the locus coeruleus of the pons, the raphe nucleus in the pontine midbrain, and SNpc in the midbrain. In the advanced stages of the disease, LB is found in the temporal cortex, limbic region, and cerebral cortex. Thus, PD is characterized not only by the abnormal accumulations and aggregation of αSyn within neuronal cell bodies and neuritis but also by the intercellular transport of aggregated αSyn  [12,13]. 

A study of the intestinal nervous system has shown that disturbances in intestinal permeability and systemic exposure to bacterial antigens induce the expression of inflammatory cytokines, such as tumor necrosis factor (TNF-α) or interleukin (IL)-1β and IL-6, which disrupt the integrity of the BBB, contribute to the accumulation of αSyn in SN and lead to the death of dopaminergic neurons [50].

Epigenetics is the study of heritable changes in gene expression that occur without alterations to the DNA sequence, linking the genome to its surroundings. In recent years, a lot of evidence has emerged that genes associated with PD are particularly prone to epigenetic dysregulation. On the other hand, in a healthy young person, the accumulation of epigenetic alterations over the lifespan in genes not associated with PD may also contribute to neurodegeneration, and these epigenetic biomarkers may be useful in clinical practice for the diagnosis, surveillance, and prognosis of disease activity in patients with PD  [51,52,53,54]. 

Some genes underlying PD loci would alter PD risk through changes to expression or splicing. Gene-level analysis of expression revealed five genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated. A further six genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects [55]. Transcriptional regulation tightly correlates with specific epigenetic marks. In X-linked dystonia-parkinsonism, three disease-specific single-nucleotide changes (DSCs) introduce (DSC12) or abolish (DSC2 and DSC3) CpG dinucleotides and consequently sites of putative DNA methylation [56]. Current research indicates that variants in the SNCA gene, exposure to pesticides, and physical activity impact the epigenome, particularly at the level of CpG methylation, so these factors are key contributors to PD risk  [57,58]. On the other hand, of the fourteen analyzed CpGs of SNCA_intron1, CpGs 16–23 were hypomethylated in PD [59]. 

Elevated αSyn levels may influence the epigenetic regulation of PD pathways, too. In sporadic PD, the gastrointestinal tract may be a site of origin for αSyn pathology; the disruption of the autophagy-lysosome pathway (ALP) may contribute to αSyn aggregation. As a result of this, aberrant methylation takes place at 928 cytosines affecting 326 ALP genes in the appendix; in addition, widespread hypermethylation was also found in the brain of individuals with PD  [60]. 

Epidemiological studies have provided evidence that exposure to organochlorine agrichemicals elevates a person’s risk for PD. A comparison of plantation workers with different terms of occupation detected seven and 123 differentially methylated loci in brain and blood cell DNA, respectively  [61]. The blood of patients with dementia with LB (DLB) shows differential methylation compared to the blood of patients with Parkinson’s disease dementia (PDD) and sets of probes show high predictive value to discriminate between variants [62]. DNA methylation patterns are established and maintained by DNA methyltransferases (DNMTs), and it was found that protein expression of DNMT1 was reduced in the cellular and mouse models of PD. Paradoxically, mRNA levels of DNMT1 were increased in these models [63].

Aberrant DNA methylation is closely associated with many aspects of the pathogenesis of PD and presents a mechanism to investigate inflammation, aging, and hematopoiesis in PD, using epigenetic mitotic aging and aging clocks. In early PD, accelerated hematopoietic cell mitosis was revealed, possibly reflecting immune pathway imbalances, which may be related to motor and cognitive progression [64]. The integration of metabolomics and epigenetics (genome-wide DNA methylation; epimetabolomics) was described after studies of the frontal lobe of people who died from PD: 48 metabolites and 4313 differentially methylated sites were identified in the primary motor cortex of people who died from PD, as compared with age- and sex-matched controls [65]. The metabolite taurine level correlated with CpG methylated sites, and bile acid biosynthesis was the major biochemical pathway to be perturbed in the frontal lobe of PD sufferers. Decreased levels of bacterially produced butyrate are related to epigenetic changes in leucocytes and neurons from PD patients and to the severity of their depressive symptoms [66].

Aberrant histone acetylation is also involved in the pathophysiology of PD. For instance, immunoblotting analyses revealed increased acetylation at several histone sites in PD, with the most prominent change observed for H3K27, a marker of active promoters and enhancers [67]. Changes in histone acetylation profile triggered by the neurotoxic mitochondrial complex II inhibitor 3-nitropropionic acid (3-NPA), were significantly different from the transcriptomic profile induced by MPP⁺ and Manganese (Mn) [68]. In a cell model of PD, αSyn significantly increased MHC-II expression, together with IFN-ɣ and IL-16 levels, which were potentiated with CUDC-907 (a dual PI3K and histone deacetylase (HDAC) inhibitor) and TMP-195 (a potent and selective inhibitor of class IIa HDAC) [69].

Histone methylation and acetylation are involved in synchronizing gene expression and protein function in neuronal cells, and manipulations of these two mechanisms influence the susceptibility of neurons to degeneration and apoptosis. Some pharmaceuticals, such as HDAC inhibitors and DNA methylation inhibitors, were developed to deal with CNS disease by targeting epigenetic components.

Noncoding RNAs consist of a very special class of epigenetic regulators. The change from viewing noncoding RNA as “junk” in the genome to seeing it as a critical epigenetic regulator in almost every human condition or disease has forced a paradigm shift in biomedical and clinical research. Small and long noncoding RNA transcripts are now routinely evaluated as putative diagnostic or therapeutic agents [70]. Long non-coding RNAs (lncRNAs) are a class of ncRNAs that have a length of 200 nt or more [71]. MicroRNA (miRNA, miR) are short non-coding RNA molecules with approximately 17–22 nucleotides in length [72]. Both lncRNA and miRNA control gene expression post-transcriptionally through either translational repression or mRNA degradation [73]. An excellent review has recently been published that highlights multiple aspects of the regulatory and diagnostic roles of miRNAs in PD: these are signaling mechanisms and epigenetic regulation; inflammation, ferroptosis, mitophagy and autophagy mediating pathways and miRNAs as biomarkers and therapeutic targets [74].