INTRODUCTION:

PD is a gradually worsening neurological condition that primarily affects movement, affecting approximately one percent of individuals over the age of sixty-five percent¹ the hallmark diseased features of parkinsonism assimilate degeneration of dopamine-producing brain cell in the SN of the ventral corpora quadrigemina and the widespread assemblage of intra-neuronal α-synuclein aggregates, known as Lewy bodies.²

Clinically, most patients with “Parkinson’s disease” display key movement-related symptoms such as slowness of movement, quivering, firmness, and loss of balance.³Along with motor challenges, non-motor symptoms are also widespread, including autonomic dysfunction, cognitive decline, and psychiatric disturbances. These may comprehend alimentary stoppage, wakefulness, mental illness, melancholy and apprehension.⁴

From a pathological perspective, Lewy bodies (LBs)—eosinophilic intracytoplasmic proteinaceous inclusions—and dystrophic Lewy neurites are observed in the surviving neurons.⁵ Microscopic examination of PD brain tissue has revealed numer of cell death, comprehend caspase-mediated cell death, sphacelus, and self-digestion, particularly among dopaminergic neurons in the SN.⁶ The detection of autophagy-related markers, such as LC3, within LBs underscores involvement as to autophagic mechanisms in parkinsonism.⁷ Similarly, elevated levels of Beclin-1, a key autophagy regulator, transpired voiced in PD brains. so that dysfunctional autophagy contributes to the assemblage of aggregated α-synuclein, possibly resulting in development of LBs.⁸

Despite the introduction of symptomatic treatments—most notably dopamine replacement therapy with levodopa and deep brain stimulation—these interventions fail to arrest the progression of PD.⁹ The ongoing persistence and deterioration of “treatment-resistant motor and non-motor symptoms” continue to pose a considerable challenge for patients.¹⁰Post-mortem studies have shown microglial activation in the brains of individuals with PD, especially in regions with prominent α-synuclein pathology.¹¹ Additionally, inflammatory mediators, including cytokines, have been detected in the brains of PD patients, and immune cell infiltration, such as CD4+ T cells, has been observed in PD animal models, highlighting the contribution of neuroinflammation to disease progression.¹²

Aggregated α-synuclein not only triggers the inflammatory responses, but also induces the synthesis of “reactive oxygen species (ROS)” that aggravate the oxidative stress and, in addition, lead to the aggregation of alpha-synuclein.¹³ These interconnected mechanisms reflect the “delicate molecular balance in the neuroinflammatory process. Glial cells”, which can either exacerbate damage or facilitate repair, play a critical role in modulating neuroinflammation and neuronal survival (Fig. 1).¹⁴

MOLECULAR MECHANISM OF PD:

1. α-Synuclein Aggregation:

Neuronal degeneration observed in “Parkinson’s disease” (PD) is linked to several molecular and cellular disruptions, including the buildup of α-synuclein, disturbances in protein quality control, excitotoxic damage, oxidative imbalance, programmed cell death, and impaired mitochondrial function.¹⁵ A prominent theory suggests that the pathological accumulation of α-synuclein plays a critical role in the degeneration of dopaminergic neurons in the nigrostriatal pathway.¹⁶ This protein is distributed across various cellular compartments—namely the cytosol, mitochondria, and nucleus—and is thought to act as a molecular chaperone involved in synaptic vesicle regulation, intracellular transport, and maintaining mitochondrial health.¹⁷ Research also indicates a possible role for α-synuclein in lipid metabolism within the brain, which may contribute to disease development. Under pathological conditions, α-synuclein monomers may misfold and form toxic oligomers, which can further aggregate into protofibrils and eventually into insoluble fibrils.¹⁸ Age-related weakening of the brain’s protein degradation systems may accelerate this process. The balance of α-synuclein within cells is primarily controlled by the “ubiquitin–proteasome system and autophagy-lysosomal” pathways.¹⁹ In addition, certain extracellular enzymes also participate in its breakdown. When these clearance mechanisms are impaired, α-synuclein can accumulate abnormally, promoting neurodegeneration.²⁰(Fig.1)

2. Oxidative stress:

“Oxidative stress (OS) plays a pivotal role” in the aging process and has a profound impact on the central nervous system (CNS).²¹ Under normal physiological conditions, reactive oxygen species (ROS) contribute positively to immune defense, gene regulation, synaptic modulation, and programmed cell death. The onset of oxidative stress occurs when the cellular antioxidant capacity is outpaced by ROS levels, leading to increased concentrations of harmful compounds.²² This imbalance can damage proteins, impair enzymatic activity, degrade lipids, and ultimately lead to the death of neurons, including dopamine-producing (DA) neurons.²³ Such oxidative damage is a contributing factor in the development of neurodegenerative disorders such as “Parkinson’s disease” (PD) and may also be involved in “Alzheimer’s disease (AD).²⁴ NADPH oxidase (NOX)” is recognized as a central ROS-producing enzyme involved in the early stages of oxidative stress and related neurodegenerative processes²⁵. Mitochondria primarily contribute to “reactive oxygen species (ROS) production, particularly, at complex I and III of the electron transport chain”. The most common form of ROS which is generated in mitochondria is the superoxide anion, which is generated by the addition of a single electron to molecular oxygen.²⁶ This superoxide can be “converted into hydrogen peroxide by manganese superoxide dismutase (MnSOD)”, and further detoxified by catalase. When ferrous iron (Fe²⁺) is present, hydrogen peroxide can “participate in the Fenton reaction, resulting in the formation of highly reactive hydroxyl radicals” capable of causing significant DNA damage and oleaginous.²⁷ Iron-related regulatory disturbance appears closely related to ferroptosis, a kind of programmed cell death attributed to iron-mediated lipid peroxidation. The hydroxyl radicals have the potential to oxidise lipids which gives rise to lipid peroxide formation and ferroptosis cell death eventually.²⁸ A reduction in glutathione levels intensifies this oxidative environment, allowing lipid peroxides to accumulate and further drive ferroptosis, which serves as a key biochemical hallmark of this process.²⁹ In addition, excessive ROS can reduce lysosomal numbers and impair autophagy, potentially promoting the accumulation of α-synuclein. Another proposed mechanism involves the oxidation of surplus cytosolic dopamine into dopamine-quinones, which may modify α-synuclein and interfere with chaperone-mediated autophagy, fostering α-synuclein aggregation.³⁰ Meanwhile, the presence of these aggregates has been linked to elevated oxidative stress within mitochondria. (Fig.1)

Fig-1: The balance of intracellular α-synuclein levels is primarily regulated through two major degradation systems: the ubiquitin–proteasome pathway and the lysosomal autophagy mechanism. When these systems are compromised—due to factors such as oxidative stress (OS), mitochondrial impairment, or neuroinflammatory responses—α-synuclein may accumulate abnormally within neurons. Additionally, mutations in genes such as LRRK2, DJ-1, Parkin, and PINK1 are known to disrupt mitochondrial integrity and elevate neuronal vulnerability, ultimately increasing cell death rates. Collectively, these findings underscore a significant interplay between oxidative stress and neuroinflammation in the progression of neurodegenerative diseases.

3) Ferroptosis:

“This iron-dependent form of programmed cell death, known as ferroptosis”, arises from imbalanced iron homeostasis combined with elevated lipid peroxidation.³¹This mechanism contributes to oxidative stress (OS) and neuronal loss and has been closely linked to the degeneration of dopaminergic neurons observed in “Parkinson’s disease”.³² The enzyme ACSL4 (“acyl-CoA synthetase long-chain family member 4”) facilitates the cytosolic conversion of coenzyme A into free polyunsaturated fatty acids (PUFAs), which are subsequently incorporated into phospholipids.³³ These PUFA-containing phospholipids become targets for oxidative enzymes such as lipoxygenases 12 and 15, leading to lipid peroxidation.³⁴ Glutathione (GSH), a key intracellular antioxidant synthesized from glutamate and cysteine, plays a vital role in inhibiting ferroptosis by blocking lipid peroxidation.³⁵ The availability of cysteine, a rate-limiting precursor of GSH, is regulated through the xCT antiporter, which imports cystine into the cell.Cysteine can also be synthesized from methionine through the transsulfuration pathway, a process safeguarded by the antioxidant enzyme DJ-1. DJ-1 prevents degradation of this pathway, supporting both cysteine and GSH production and thereby functioning as a natural suppressor of ferroptosis.³⁶(Fig.2)

Glutathione peroxidase-4 is distinct in its ability to convert lipid hydroperoxides into lipid alcohols under normal physiological conditions, utilizing reduced glutathione (GSH) as a cofactor. Experimental suppression of glutathione peroxidase-4.³⁷by way of illustration through RAS-selective lethal 3 (RSL3)-is a common method to induce ferroptosis in research settings. The cellular features triggered by ferroptosis mirror the pathological alterations seen in PD, and several ferroptosis-associated genes have been found to correlate with the disease.³⁸ Notably, iron and α-synuclein often co-accumulate in Lewy bodies in the midbrains of PD patients. Since α-synuclein can bind metal ions, interaction with iron causes structural changes that promote its aggregation.³⁹

Upon activation, microglia store iron and emit inflammatory cytokines, fostering enhanced iron accumulation in the CNS environment. In this context, there is increased expression of proteins involved in iron uptake and storage such as “divalent metal transporter 1 (DMT1), iron regulatory protein 1 (IRP1), and transferrin receptor 1 (TfR1)” responsible for iron uptake, is highly expressed, the iron-exporting protein FPN1 is significantly diminished in expression.⁴⁰ This imbalance promotes excessive iron retention in neurons. Furthermore, microglial NADPH oxidase (NOX) contributes to ROS production, exacerbating oxidative stress and facilitating ferroptotic death in DA neurons.⁴¹ Inducible nitric oxide synthase (iNOS), which becomes highly expressed in microglia during inflammation, can inhibit 15-lipoxygenase, offering a protective mechanism against ferroptosis.⁴²

Astrocytes also play a role in managing iron levels through protein cascades, including those involving ceruloplasmin (CP).By converting Fe² to Fe³,ceruloplasmin facilitates the export of iron, owing to its ferroxidase enzymatic role.⁴³ However, this enzymatic function is markedly reduced-by nearly eighty percent-in the “substantia nigra (SN) of PD patients, contributing to” pathological iron accumulation and subsequent neuronal degeneration.⁴⁴ Additional evidence of “Parkinson’s disease”, ferrous-related toxicity is marked by elevated “expression of heme oxygenase-1” in astrocytes and microglial cells. In response to oxidative stress, reactive astrocytes may counteract neuronal damage by producing antioxidants such as GSH and metallothioneins.⁴⁵ “Activation of the transcription factor Nrf2 in astrocytes” further enhances antioxidant defense by upregulating the expression of genes responsible for the synthesis of GSH and metallothionein’s, providing neuroprotection to DA neurons under oxidative conditions.⁴⁶(Fig.2)

Fig-2: “Inflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), which are secreted by activated microglia and astrocytes, contribute to neuronal iron accumulation by enhancing the expression of increase in divalent metal transporter 1 expression and a decrease in ferroportin 1, the main proteid responsible for exporting ferrous. In contrast, brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF)”, released from activated astrocytes, play a neuroprotective role by lowering DMT1 expression and thereby limiting iron uptake in neurons. Moreover, reactive oxygen species (ROS) generated by activated microglia intensify oxidative stress (OS) within neuronal cells. To counter this, astrocytes activate antioxidant defenses through the upregulation of nuclear factor erythroid 2–related factor 2 (Nrf2) and the secretion of metallothioneins, both of which enhance neuronal resilience against oxidative damage.

4) Mitochondrial dysfunction:

“Mitochondrial dysfunction is increasingly understood to be a central factor in the development of Parkinson’s disease (PD)”. A wide range of studies have shown that defects in mitochondrial function contribute significantly to the loss of dopaminergic neurons and promote sustained “production of reactive oxygen species (ROS)”.⁴⁷ The earliest indication of this link came from research demonstrating that MPTP, a neurotoxic compound, specifically blocks mitochondrial complex I activity.⁴⁸ Similar neurodegenerative outcomes have been observed with other Inhibitors targeting mitochondrial “complex I including rotenone, pyridaben, fenpyroximate, and trichloroethylene” have demonstrated similar neurotoxic effects.⁴⁹Moreover, animal models overexpressing α-synuclein appear more sensitive to these mitochondrial toxins than those lacking the protein, suggesting that the presence of α-synuclein in mitochondria enhances cellular toxicity.⁵⁰Mitochondrial dysfunction may also stem from disrupted regulation of transcription factors involved in mitochondrial biogenesis. A critical player in this process is “PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1 alpha)”, which governs the formation and maintenance of mitochondria.⁵¹ Experimental evidence shows that mice lacking PGC-1α exhibit increased vulnerability to MPTP, whereas its overexpression offers neuroprotection.⁵²

In addition, genetic mutations in certain key genes—including Parkin, DJ-1, PINK1, and LRRK2—have been closely linked to mitochondrial failure in PD.⁵³The Parkin gene encodes an E3 ubiquitin ligase, and animals without functional Parkin are highly sensitive to mitochondrial toxins like rotenone.⁵⁴ PINK1 mutations, which are responsible for a recessive form of PD, disrupt mitochondrial respiration and ATP synthesis, and also encourage α-synuclein buildup.⁵⁵ Loss of PINK1 impairs mitochondrial positioning and blocks mitophagy, the selective autophagy of damaged mitochondria.⁵⁶ Studies in Drosophila have demonstrated that Parkin and PINK1 function in a shared pathway, with PINK1 operating upstream of Parkin.⁵⁷

When mitochondria become depolarized, they signal for Parkin recruitment from the cytoplasm, initiating mitophagy.⁵⁸ This process depends on the stabilization of PINK1 on the mitochondrial surface and subsequent activation of related signaling proteins.⁵⁹One such regulator is “SHP2 (Src homology 2 domain-containing phosphatase-2)”, which has been shown to be essential for Parkin’s translocation and ubiquitin ligase activity.⁶⁰ Inhibition of SHP2 disrupts this mechanism, potentially through interference with tyrosine dephosphorylation. Interestingly, the drug lovastatin has been identified as a SHP2 activator and may offer therapeutic potential in PD treatment.

Additionally, DJ-1 gene mutations, responsible for a rare inherited form of PD, lead to increased sensitivity to oxidative damage. Both mouse models and human cases with DJ-1 loss-of-function show impaired mitochondrial respiration.⁶¹On the other hand, mutations in the LRRK2 gene are associated with dominant forms of PD. In older mice carrying the G2019S mutation in LRRK2, researchers have noted abnormal mitochondrial structures in the striatum, findings that are also mirrored in dopaminergic neurons of C. elegans with the same mutation.⁶² Furthermore, LRRK2-linked mitochondrial defects may involve alterations in mitochondrial fission, a process regulated by dynamin-related proteins.⁶³

5) Neuroinflammation:

Analyses of postmortem brain tissue from individuals with “Parkinson’s disease” (PD) have consistently shown that neuroinflammation plays a central role in the disease.⁶⁴ “Both innate and adaptive immune responses contribute to the progression of PD.⁶⁵Microglia are the brain's main innate immune cells”, and when they are activated, they elevate the amounts of chemicals like NLRP3 and NF-κB. This makes cytokines that promote inflammation, like IL-1β and TNF-α, to be released.⁶⁶Elevated levels of activated microglia have been observed in the midbrain and putamen of patients in the early stages of PD, correlating with reductions in dopamine transporter binding.⁶⁷ Although chronic inflammation is well-established in PD pathology, the specific mechanisms remain only partially understood. One hypothesis suggests that misfolded “α-synuclein acts as a damage-associated molecular pattern (DAMP)”, activating proinflammatory responses after entering cells via toll-like receptor 2 (TLR2).⁶⁸ (Fig.3)

Additionally, molecules like mitochondrial reactive oxygen species (ROS), IL-1α, and other DAMPs released from injured neurons may activate pattern recognition receptors (PRRs), triggering NLRP3 activation and the subsequent increase in IL-1β production,thereby boosting the innate immune response.⁶⁹Sustained immune activation may significantly contribute to microglia-associated neuroinflammation in “Parkinson’s disease”.⁷⁰Experimental models, such as those using 6-hydroxydopamine (6-OHDA), have demonstrated a shift in microglial behavior from the anti-inflammatory M2 phenotype to the proinflammatory M1 phenotype during disease progression.⁷¹ Once polarized to M1, microglia promote inflammation through “NF-κB activation”, leading to the expression of inflammatory genes such as interleukins and along with procaspase-1, both of which play roles in forming the “NLR family pyrin domain containing 3 inflammasome” and generating active Interleukin-1 beta. Other harmful molecules like inducible nitric oxide synthase (iNOS) and TNF-α, also produced by M1 microglia, further promote neuronal damage.^72-73 Notably, deletion of TLR4 in animal models was shown to reduce microglial activation and protect “dopaminergic neurons in the substantia nigra, suggesting that TLR4 plays a pivotal role in the neuroinflammatory processes associated with PD”.⁷⁴

Studies have demonstrated that T lymphocytes—especially CD4 and CD8 subsets-penetrate the substantia nigra in individuals with “Parkinson’s disease”, with CD8 cells being more prevalent during the early stages and declining as the condition progresses.⁷⁵ CD4 T cells have also been shown to contribute to neurodegeneration, as changes in their activity and increased numbers of HLA-DR microglia have been observed in PD brains.⁷⁶ The involvement of Th17 cells, a subset of CD4 T cells, has also been implicated in promoting neuronal vulnerability via IL-17-induced NF-κB signaling pathways.⁷⁷ Removing or repressing CD4 T cells also affects the amount of MHC-II that myeloid cells in the brain and spinal cord make. This has to do with keeping TH-expressing neurons in the substantia nigra pars compacta (SNpc) safe.⁷⁸

Fig-3: The diagram depicts multiple mechanisms “implicated in the pathogenesis of “Parkinson’s disease” (PD).

A) Neuroinflammation: Microglia, the brain’s resident immune cells, are activated by various” factors such as environmental toxins, infectious agents, peripheral immune signals (e.g., CD4<sup>+</sup> T cells), aging, and prolonged psychological stress. These triggers can induce different microglial phenotypes. The M1 phenotype is pro-inflammatory and may exert harmful effects on neurons by releasing cytokines like “IL-1β, IL-6, IFN-γ, and TNF-α, along with complement proteins, inducible nitric oxide synthase (iNOS), and reactive oxygen species (ROS). Conversely, M2 microglia are believed to possess neuroprotective, anti-inflammatory properties, producing factors such as IL-10, TGF-β, brain-derived neurotrophic factor (BDNF), and arginase-1 (Arg-1). The interplay between microglia and astrocytes may modulate the temporal release of cytokines and growth factors, contributing to PD-associated neuropathology. B) Autophagy: Inflammatory processes influence all forms of autophagy, including macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Mutations in certain genes may disrupt chaperone-mediated autophagy (CMA)”, leading to the buildup of α-synuclein within cells. Mitophagy, a selective form of autophagy that eliminates damaged mitochondria, relies heavily on proteins such as PINK1 and Parkin, which help preserve mitochondrial integrity and regulate the mitophagic process. C) Oxidative Stress: Dopaminergic neurons are susceptible to oxidative damage due to dopamine (DA) auto-oxidation, which generates reactive species and DA quinones. Aging and exposure to certain neurotoxins can impair mitochondrial function, increasing ROS production and contributing to cellular oxidative stress and neuronal injury.

6) Parkin (OMIM 602544; PARK2):

The involvement of the parkin gene has been firmly established in the onset of autosomal recessive juvenile “Parkinson’s disease” It was first identified through genetic mapping studies in consanguineous Japanese household. Since then, mutations in parkin have been found to account for nearly fivty percent of early-onset familial PD cases and approximately ten percent of all young-onset Parkinsonism.⁷⁹ While most cases linked to parkin mutations are inherited recessively, some families show atypical inheritance patterns, suggesting other genetic or environmental interactions. Additionally, heterozygous mutations, or haploinsufficiency, may also elevate susceptibility to the disease.⁸⁰

The parkin gene produces a protein made up of four hundred sixty four amino acids, which acts as an E3 ubiquitin ligase.Structurally, the protein contains an “N-terminal ubiquitin-like (UBL) domain.As an E3 ligase, parkin plays a central role in the ubiquitin-proteasome system” by tagging damaged or misfolded proteins for degradation.It associates with several E2 ubiquitin-conjugating enzymes, such as UBE2L3, UBE2L6, UBC6, and UBC7. These interactions enable the transfer of ubiquitin molecules to substrates, leading to either degradation or other regulatory effects.⁸¹

A broad spectrum of parkin gene alterations has been identified, including single-nucleotide changes, minor insertions or deletions, and extensive chromosomal modifications. Most of these mutations are considered loss-of-function, impairing the protein's ability to interact with its substrates or E2 enzymes, and ultimately compromising its E3 ligase activity.⁸² As a result, toxic proteins that should be degraded accumulate, contributing to neuronal damage. (Fig.4)

Parkin polyubiquitinates certain neuronal proteins, such as CDCrel-1, Pael-R, synphilin-1, cyclin E, and synaptotagmin XI. People with “Parkinson’s disease” typically have Lewy bodies, which are aggregates of protein. They have been found to contain many of these substrates.⁸³ For instance, co-expression of α-synuclein and synphilin-1 in cell models leads to the formation of inclusion bodies, which parkin helps to ubiquitinate. This function suggests a possible protective mechanism against the buildup of toxic protein aggregates.⁸⁴

Experimental studies in parkin-deficient mice and Drosophila models have revealed important insights. Although parkin knockout mice do not exhibit classic PD symptoms, they show early mitochondrial dysfunction and oxidative stress, hinting at an underlying pathophysiological role for parkin in maintaining mitochondrial integrity.⁸⁵ In flies, the absence of parkin results in motor deficits, shortened lifespan, and infertility, all linked to mitochondrial abnormalities. These findings highlight parkin’s broader function beyond protein degradation, particularly in regulating mitochondrial health and protecting against oxidative stress.⁸⁶

Overexpression studies further support parkin’s neuroprotective role. When overexpressed in cultured cells or animal models, parkin reduces cell death caused by mitochondrial toxins, proteasome inhibition, and overexpression of toxic proteins like α-synuclein or Pael-R. This strongly supports the notion that parkin acts as a cellular defense mechanism and may serve as a potential therapeutic target in “Parkinson’s disease”.⁸⁷

7) UCH-L1 (OMIM191342; PARK5; Neuron-Specific PGP9.5):

A rare mutation (I93M) in the UCH-L1 gene, which encodes a neuron-specific deubiquitinating enzyme, was identified in a familial “Parkinson’s disease” (PD) case, though its pathogenic role remains unclear due to incomplete penetrance.⁸⁸ A common variant, S18Y, has been associated with reduced PD risk in some studies, though results are inconsistent.UCH-L1 is involved in maintaining the balance of free ubiquitin by breaking down polyubiquitin chains and may also function as a ubiquitin ligase. Its presence in Lewy bodies and its ability to influence α-synuclein accumulation point to a potential role in PD.⁸⁹ The I93M mutation reduces its enzymatic activity, possibly impairing the ubiquitin-proteasome system (UPS) and promoting toxic protein buildup. In contrast, the S18Y variant may offer protection by maintaining hydrolase activity while reducing ligase function, highlighting the importance of UCH-L1 in protein regulation and its possible involvement in “Parkinson’s disease” mechanisms.⁹⁰(Fig.4)

8) PINK1 (OMIM608309; PARK6; PTEN-Induced Putative Kinase 1):

A genome-wide homozygosity mapping using a large Sicilian family, with four individuals affected with early-onset Parkinson disease (PD) was able to find a common genetic block of unusual size (12.5 cM on chromosome 1p35p36). This region was found significant with further research using other related families with the same genetic pattern which eventually led to the identification of mutation in the PINK1 gene.⁹¹ Although several novel mutations in PINK1 were initially reported in familial early-onset PD cases, these variants appear to occur less frequently than parkin gene mutations in similar patient groups. Additionally, no significant association was observed between PINK1 polymorphisms and idiopathic PD in a broad European sample.⁹²

The PINK1 protein consists of 581 amino acids and includes a mitochondrial localization signal at the N-terminal, along with a conserved kinase domain resembling that of the Ca²⁺/calmodulin-dependent kinase family.Studies involving elevated expression levels of PINK1 suggest its localization within mitochondria in cells grown in culture Although its exact physiological function remains under investigation, mutations in or near the kinase domain are believed to impair mitochondrial integrity, suggesting that PINK1 dysfunction may contribute directly to PD pathogenesis through loss of kinase activity.⁹³

Fig-4: Initially, ubiquitin (Ub) monomers are activated by an “E1 enzyme (ubiquitin-activating enzyme), which then transfers them to an E2 enzyme (ubiquitin-conjugating enzyme). Specific substrates” whether misfolded or functionally normal—are recognized by an E3 ligase, “such as parkin, which promotes the transfer of ubiquitin from the E2 enzyme to the target protein”. Through successive covalent additions, ubiquitin molecules are linked to lysine (K) residues on preceding ubiquitins, forming polyubiquitin chains. Chains constructed via K29 or K48 linkages signal for the destruction of the tagged protein by the 26S proteasome in a process requiring ATP. This results in the protein being broken down into short peptides. Following degradation, deubiquitinating enzymes (DUBs), such as UCH-L1, cleave the ubiquitin chains, recycling them into free monomers for reuse in the system.Beyond targeting proteins for degradation, ubiquitin modification serves several additional roles. Proteins can be tagged with a single ubiquitin (mono-ubiquitination), multiple mono-ubiquitins, or polyubiquitin chains linked via K63, which are involved in non-degradative cellular processes such as DNA repair, membrane trafficking, endocytosis, and regulation of gene expression

9) DJ-1 (OMIM 602533; PARK7):

Genetic investigation in a family affected by early-onset “Parkinson’s disease” (PD) identified a significant segment on chromosome 1p36, which led to the identification of mutations in the Parkinson disease protein 7 gene Although several types of mutations—including missense, splicing errors, and small deletions—have been identified in familial PD cases, such alterations are very uncommon and represent less than one percent of all early-onset PD instances.⁹⁴ Moreover, current research suggests that Parkinson disease protein 7 gene variants do not significantly influence the risk of idiopathic PD.⁹⁵

The Parkinson disease protein 7 (PARK7) gene produces a protein made up of 189 amino acids, belonging to the DJ-1/ThiJ/PfpI protein family, and is ubiquitously expressed distributed throughout the body, including neurons and glial cells of the brain. While it is not typically located in Lewy bodies, Parkinson disease protein 7 does co-localize with pathological proteins in other neurodegenerative diseases, implying its involvement in broader cellular dysfunctions.⁹⁶

Structurally, Parkinson disease protein 7 resembles stress-related bacterial proteins and exists as a stable dimer. It may have dual biochemical roles, acting as both a molecular chaperone and a weak protease, though its natural substrates remain unclear.⁹⁷ An important characteristic of Parkinson disease protein 7 is its ability to react to oxidative stress Under such conditions, it undergoes modifications—especially at cysteine residue 106—that alter its isoelectric point and promote mitochondrial localization. These changes help protect cells from damage and may also trigger interactions with parkin, another neuroprotective protein.⁹⁸(Fig.4)

Loss-of-function mutations, such as L166P, destabilize Parkinson disease protein 7, disrupt dimer formation, and increase degradation, thereby reducing its ability to counteract oxidative insults. These findings suggest Parkinson disease protein 7 plays a crucial defensive role in maintaining mitochondrial integrity and preventing oxidative damage.⁹⁹ Additionally, its potential participation in protein quality control pathways, including the ubiquitin-proteasome system (UPS), highlights its importance in safeguarding neurons against various cellular stressors.

10) Gut dysbiosis:

The role of gut microbiota in the onset and advancement of neurological disorders has emerged as a significant focus in current research. The microbiota of gut and brain interact through complex circuits that are constituted by CNS, ENS, autonomic and the hypothalamic–pituitary–adrenal (HPA) axis. This bidirectional interaction is mediated by immune signals, hormones, microbial metabolites, and afferent neural pathways.¹⁰⁰The gut microbiota can modulate inflammatory responses within the ENS, contributing to the development of “Parkinson’s disease” (PD). In individuals with “Parkinson’s disease”, increased concentrations of intestinal biomarkers—including zonulin and alpha-1-antitrypsin, which signal impaired gut barrier function, as well as calprotectin, an indicator of intestinal inflammation—have been documented.¹⁰¹Additionally, specific microbial taxa have been strongly associated with systemic inflammatory responses. For instance, an increased presence of Verrucomicrobiaceae correlates with higher levels of interferon-gamma (IFN-γ) in plasma, while Bacteroides abundance is associated with elevated tumor necrosis factor (TNF) levels. Conversely, Roseburia appears to support immune balance by upregulating innate immune genes and suppressing the NF-κB pathway.¹⁰²Through their influence on gut inflammation and barrier function, microbial communities and their byproducts may be implicated in PD pathogenesis.¹⁰³Among these byproducts, lipopolysaccharide (LPS) is particularly important, as it contributes to both increased α-synuclein aggregation in the ENS and heightened intestinal permeability.¹⁰⁴ In experimental models, LPS exposure in Thy1-α-synuclein transgenic mice led to reduced expression of tight junction proteins, such as zona occludens-1 and E-cadherin, highlighting the gut–brain interplay in PD progression.¹⁰⁵ Further evidence comes from findings that infection with curli-producing bacteria enhances α-synuclein accumulation in enteric and central neurons, leading to inflammatory responses. There have been a number of studies on animals that demonstrate that α-synuclein aggregates can travel along the gut–brain axis from the gut to the brain. When α-synuclein is injected into the stomach wall, it makes the CNS act in ways that are not typical.¹⁰⁶ However, pathological developments are not exclusively reliant on these bidirectional pathways. Degenerative processes may occur separately within the “enteric nervous system (ENS) or central nervous system (CNS)”. Drawing from their research, Arotcarena and colleagues proposed a model in which naturally occurring α-synuclein can move in both directions between the brain and the gut through the body's circulatory system.¹⁰⁷(Fig.5)

Fig-5: “Damage-associated molecular patterns (DAMPs), such as α-synuclein, activate the innate immune system by binding to pattern recognition receptors (PRRs)” found on microglial cells. This interaction prompts microglial activation, which in turn elevates levels of NF-κB and NLRP3, resulting in increased cytokine production. Meanwhile, imbalances in gut microbiota (gut dysbiosis) communicate with both the central and enteric nervous systems through various pathways including microbial metabolites, hormonal signals, and immune responses, thereby contributing to neuroinflammation.

CONCLUSION:

Numerous region-specific molecular and cellular mechanisms actively contribute to the development of “Parkinson’s disease”. These mechanisms not only function individually but also interact and influence one another in both healthy and disease conditions. The activation of microglia and astrocytes can trigger neuroinflammation and promote the degeneration of neurons in the substantia nigra. Oxidative stress is another key factor, often arising from environmental exposures or age-related mitochondrial decline, resulting in the generation of “reactive oxygen species (ROS)”. In dopaminergic neurons, dopamine undergoes auto-oxidation, serving as a major internal source of ROS and contributing to oxidative stress. The elevated energy requirements of these neurons with age may further impair mitochondrial function and enhance oxidative damage. Mitophagy plays a vital role in eliminating damaged mitochondria from substantia nigra neurons; however, mutations that disrupt autophagy can lead to intracellular buildup of toxic proteins. The influence of aging on these molecular and cellular processes remains poorly understood, highlighting the need for future research to unravel how these pathways interact under normal and pathological conditions, which is essential for developing targeted therapies.

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Received on 27.08.2025 Revised on 08.11.2025

Accepted on 15.12.2025 Published on 12.02.2026

Available online from February 14, 2026

Res.J. Pharmacology and Pharmacodynamics.2026;18(1):35-45.

DOI: 10.52711/2321-5836.2026.00005

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