Oxidative stress and Parkinsons disease -
Iron is known to raise ROS production through generating hydroxyl radicals, leading to α-synuclein-mediated reactive species formation in SN via Fenton reaction and redox-active iron accumulation in neuromelanin granules in SN There is considerable evidence suggesting a key role of ROS in mitophagy.
Light-induced activation of mitochondria-targeted photosensitizer may cause selective ROS-mediated damage to a subset of mitochondria and subsequently trigger mitophagy in both cell lines and rodent neurons In vitro studies have demonstrated that mild and transient oxidative stress can trigger mitophagy but not non-selective autophagy Downregulation of mitochondrial fusion can spatially isolate damaged mitochondria for efficient removal by mitophagy, highlighting the selectivity of oxidative conditions in a ROS signalling cascade that dominantly triggers selective mitophagy Our own studies found that inhibition of ROS burst attenuated mitophagy at a couple of stages, i.
PINK1-dependent Parkin translocation to mitochondria and elimination of mitochondria through autophagy Interestingly, chronic low-dose treatment of mitochondrial uncoupler failed to stimulate ROS upsurge and Parkin translocation to mitochondria despite bringing PINK1 protein to a comparable level as acute high-dose treatment.
Given the indispensable role of PINK1 in the initiation of mitophagy, there is the possible modification of ROS on PINK1 in the process of mitophagy Being the primary source of cellular ROS and the central focus of mitophagy, mitochondria are the crux of a number of signalling pathways linking ROS and mitophagy , ROS are a double-edged sword, possessing bidirectional impacts on autophagic flux.
Generally, excessively high levels of ROS specifically trigger general autophagy over mitophagy In contrast, moderate levels of ROS may trigger mitophagy likely through the activation of specific signalling pathways and redox signalling 40 , with mitophagy in turn possessing neuroprotective effect on disease progression 66 , Identifying the bridges linking ROS and mitophagy is crucial for establishing their roles in PD pathogenesis and postulate potential therapeutic avenues using these interplays.
Substantial evidence suggests that ROS H 2 O 2 acting upstream of this master regulator of redox balance, NF-κB, releases its NF-κB inhibitor IκB via H 2 O 2 oxidation leading to NF-κB activation Recently, it was found that NF-κB may promote mitophagy through inducing p62 expression to attenuate mitochondrial damage triggered by NLRP3-inflammasome activator.
The same study suggested that NF-κB, through this anti-inflammatory pathway, directly affects Parkin-mediated mitophagy A study by Duan et al. identified several NF-κB-binding sites within the PINK1 promoter and demonstrated that NF-κB overexpression or administration of NF-κB activator upregulated PINK1 at transcription level TRAF6, an E3 ligase that acts as a transducer of the NF-κB pathway, and its related NF-κB activation may activate PINK1 cytosolic form to promote non-selective mitophagy through stabilization by enhanced Lyslinked ubiquitination In addition, NF-κB may promote RIPK1 translocation to the mitochondria where it forms a complex with PINK1 and phosphoglycerate mutase family member 5 PGAM5 that stabilizes and activates PINK1, eventually inducing mitophagy p38 MAPK belongs to the family of mitogen-activated protein kinases MAPKs and is responding to stress stimuli, including inflammatory cytokines and oxidative stress Under the canonical pathway of activation, ROS signalling by oxidative stress specifically oxidize antioxidant protein thioredoxin TRX and disassociate it away from the critical component ASK-1, allowing for ASK-1 dimerization and autophosphorylation, activating p38 pathway MAPK14, one of the four p38 isoforms, and its upstream signalling pathways are identified to be required in mammalian cells for both starvation- and hypoxia-induced mitophagy, but not macroautophagy, demonstrating the selectivity of this pathway A recent study by Qu et al.
Additionally, our own study identified that inhibition of p38 signalling pathway halted mitophagy progression driven by ROS even after Parkin relocated to mitochondria, further corroborating the hypothesis of MAPK having a significant influence on upregulating ROS-mediated mitophagy Nrf2 nuclear factor erythroid 2-related factor 2 is a redox-regulated transcription factor, a core element in the Nrf2-Antioxidant Response Element ARE related pathways.
Their regulation can be either Kelch-like ECH-associated protein 1 Keap1 -dependent or Keap1-independent via phosphorylation by Casein kinase II, protein kinase C, glycogen synthase kinase 3β etc These pathways are identified to mediate oxidative stress response and are established to be dysregulated in aging and neurodegenerative diseases, including PD Nrf2 pathway activation in PD was observed at a systemic level, likely to counteract oxidative stress Oxidative stress may deprive Keap of its ability to ubiquitinate Nrf2 by modifying key cysteinyl residues leading to nucleus transport of Nrf2.
Accumulated Nrf2 subsequently activates a body of antioxidant enzymes, acting as a critical master regulator for a broad set of oxidative stress responses Oxidative stress triggered Nrf2 binds to ARE located in the p62 promoter, with p62 possibly activating Nrf2 and driving its own transcription in a positive feedback cycle Alternatively, another study suggests that p62, in an Nrf2-dependent manner, recruits two subunits of a cullin-RING ubiquitin Keap1 and Rbx1 to mitochondria, promoting mitochondrial ubiquitination and subsequently mitophagy in a parkin-independent manner Sirtuins relevancy in PD context includes a variety of SIRTs appearing to alter mitophagy in PD models in addition to their expression dysregulated in PD patient samples.
For instance, decreased SIRT3 was found in the fibroblasts from PD patients and SIRT5 was accumulated in idiopathic PD fibroblast cells, with both these sirtuins being mitochondrial proteins The relationship between sirtuins SIRT and ROS, is uniquely complex and contested, with current evidence indicating that SIRT4 conditionally upregulates or suppresses ROS; SIRT1, SIRT3 and SIRT5 function against ROS; SIRT2, SIRT6, and SIRT7 mediates critical oxidative stress genes and mechanisms In addition, SIRT2-mediated mitophagy regulated via ATG32 is identified to be essential in α-synuclein toxicity in yeast samples , implicating this ROS-mitophagy interplay in PD context.
Interestingly, another study identified SIRT3 effect of inducing mitophagy by upregulating BNIP3 expression, this mitophagy modulating activity further tied with ERK-CREB signalling pathway Fig.
ROS function upstream of intracellular signalling pathways which involve several key mediators NF-κB, p38 MAPK, mTOR, Nrf2, SIRT to regulate mitophagy.
Mutations in the parkin and PINK1 account for the most common causes of autosomal recessive early-onset Parkinson disease EOPD. Early studies exploring functions of Parkin and PINK1 revealed that defects in Parkin or PINK1 result in enhanced ROS production in mouse brain or patient fibroblast , suggesting that Parkin and PINK1 may confer protection to neurons by attenuating ROS-related neurotoxicity.
Overexpressed parkin in cultured cell lines can eliminate the entire mitochondrial network in cells, eradicating detrimental factors released from damaged mitochondria Although dramatic mitophagy is not practicable in neurons, evidence of ROS inhibition through mitophagy in a physiological context has been garnered.
AMPKα2 may interact with phosphorylated PINK1 and trigger Parkin recruitment and subsequent mitophagy, leading to reduced ROS production and apoptosis of cardiomyocytes Inhibition of PINK1 accumulation on mitochondria by morphine led to mitophagy defect and excessive ROS accumulation in spinal cord neurons Mutations in the gene encoding α-synuclein SNCA cause autosomal-dominant PD through point mutations, including A53T, E46K, H50Q etc, as well as copy number variations duplication or triplication α-synuclein role in ROS includes its accumulation on mitochondria via TOM20 leading to an excessive generation of ROS, with pathogenic a-synuclein-TOM20 interaction confirmed in PD post-mortem samples α-synuclein delays mitophagy by targeting the N-terminus of Miro, leading to excessive and abnormal Miro accumulation on the mitochondrial surface Upregulated production of ROS and reactive nitrogen species RNS are present in iPSCs carrying α-synuclein A53T mutation relative to isogenic control lines α-synuclein E46K mutation was also identified to result in oxidative stress accumulation in SN DA neurons, likely increasing neuronal vulnerability towards mitochondrial impairment by mitochondrial toxins Both A53T and E46K mutations promoted mitophagy through increasing α-synuclein accumulation on mitochondria, primarily through cardiolipin externalization to the OMM DJ-1 gene has been identified to be mutated in autosomal recessive PD.
DJ-1 protein acts as a neuroprotective factor by directly eliminating hydrogen peroxide, while cells expressing DJ-1 carrying PD-related mutations are sensitive to oxidative effects 10 , Interestingly, as a sensor for oxidative stress, DJ-1 protein is susceptible to the formation of adducts with PD-relevant dopamine This relationship is theorized as a key susceptibility factor within PD-relevant A9 neurons in SN region that contain dopamine susceptible to ROS-induced adduct formation by DJ-1, further supported by in vivo evidence of elevated α-synuclein aggregates in DJ-1 deficient mice leading to the increased oxidized form of DA 10 , LRRK2, is a multifunctional enzymatic kinase, GTPase etc , scaffolding protein LRRK2 GS is a common genetic cause for familial and sporadic PD in caucasian populations , whereas in Asian population, LRRK2 ST, RP, and GR variants are associated with increased risk and lowered onset age of PD iPSC-derived neurons carrying GS mutation was shown to upregulate the expression of key genes related to oxidative stress-response and α-synuclein levels Our group have shown that quenching ROS through either genetic manipulation expressing peroxiredoxin-3 or administration of chemical antioxidant effectively rescued PD phenotypes in neuronal and Drosophila models, suggesting that ROS play a crucial role in LRRK2 pathogenesis.
LRRK2 mutations possess a complicated relationship with mitophagy, as the same GS mutations have demonstrated various mechanisms of mitophagy alterations, from increasing mitophagy through histone deacetylase activation , or in contradiction, to decreasing mitophagy probably through compromised Miro removal 7 , sirtuin activity or aberrant RAB10 phosphorylation Regardless of the uncertainty of specific regulation, which is likely context-dependent, it can be agreed that LRRK2 mutations, particularly GS, result in aberrant mitophagy within the PD context, likely contributing to its increased mitochondrial vulnerability and overall neurodegeneration Glucocerebrosidase GBA1 gene mutation is associated with a to fold increased PD development risk LP mutation in GBA has been established to induce mitochondrial dysfunctions, including altered mitophagy activation, autophagy flux and ROS levels Specifically, LP mutation in GBA has been identified to inhibit two critical areas related to mitophagy, namely mitochondrial priming and autophagic removal of the organelle Mitophagy induction is identified to enhance transcription factor EB TFEB expression leading to increased GBA1 expression.
The involvement of mitophagy in lysosomal biogenesis suggests a positive feedback loop, with GBA mutations inducing dysfunctions within this system In addition, dysfunctional mitophagy and excessive oxidative stress have been identified in post-mortem tissue of PD patients with GBA mutations , further linking the effects of GBA on ROS-mitophagy interplay in PD context.
In our review, the selection of genes we focus on reflect the most well-documented PD-related genes with regards to how they are functionally linked to mitophagy and ROS. However, genome-wide association study GWAS , , have revealed a host of relatively novel risk loci and their genes, with limited but emerging evidence that some could be implicated in both mitophagy and ROS, including VPS13C and SREBF1 We speculate that evidence of genetic variants in PD relevant context could increase in the coming years.
We have highlighted a few PD genes that are associated with both aberrant ROS accumulation and defective mitophagy. The body of the evidence above clearly proves that the abnormalities in these two aspects are universal and critical in PD. However, more studies are warranted to determine which factor is the major culprit for PD pathogenesis and how the entanglement of these two factors contribute to PD pathogenesis.
Therefore, both factors have to be taken into account to deliver effective therapy when designing a strategy to tackle PD. For instance, KH, a chemical derivative of a water-soluble form of vitamin E, enhanced mitophagy in neurons from subjects with or without Parkin mutation, suggesting its pro-mitophagy effect in a Parkin-independent manner KH exerts its anti-oxidative effects through direct interaction with peroxiredoxins , while peroxiredoxin 3 and peroxiredoxin 6 have been found to be involved in mitophagy.
Another study showed that mitochondria-targeted antioxidant, MitoQ rescued mitophagy, mitochondrial dysfunction and apoptosis through Nrf2 and PINK1 rather than its direct antioxidative effect Thus, the paradoxical pro-mitophagy effect of antioxidant may be attributed to its specific effects on mitophagy-related signalling pathways or molecules instead of its role in suppressing ROS.
In addition, ROS may directly oxidize ATG3 and ATG7 to prevent LC3 lipidation, eventually impairing autophagy Given that Atg3 and Atg7 also play indispensable roles in mitophagy, it is therefore conceivable that antioxidants may suppress the oxidation of these autophagy-related proteins to promote mitophagy in a context-dependent manner.
The success of antioxidant in promoting mitophagy indicates the potential of the therapeutic strategy for PD by promoting mitophagy while inhibiting ROS. Clinical trials throughout the decades of antioxidants creatine , vitamin E , coenzyme Q 10 , etc in PD have not provided conclusive evidence that they are neuroprotective.
One possible reason we postulate for the failure of antioxidants could be that blockage of signalling pathway necessary for mitophagy activation by undue inhibition of ROS is unlikely to be optimal against neurodegeneration.
Promoting mitophagy by direct induction of ROS may not be ideal strategy either given the high volume of evidence showing the detrimental effects of ROS on cellular health, on account of its ability to exacerbate oxidative stress damage in PD 9.
Targets in the downstream signalling of ROS which can simultaneously activate protective mitophagy, while minimizing the harm of ROS may be potentially utilized in PD therapeutics.
Melatonin N-acetylmethoxytryptamine has been shown to increase phosphorylation of Akt and NF-κB, leading to PINK1-dependent protective mitophagy Melatonin may also upregulate NRF2-induced mitophagy to protect against neuronal apoptosis in subarachnoid haemorrhage SAH The ROS levels, initially increased by high glucose conditions and necessary in order to stimulate mitophagy via Akt and NF -κB pathways, were subsequently attenuated by melatonin-induced PINK1-dependent mitophagy Melatonin has been well-documented to function against ROS and RNS, but may have pro-oxidant capabilities under specific conditions Pioglitazone, an anti-diabetic drug for Type 2 diabetes mellitus T2DM under the category of thiazolidinediones TZDs , increases PINK1 expression via NF-κB activation and enhances mitophagy.
It protects against mitochondrial dysfunction induced by toxins and reduces ROS in a chronic kidney disease study , Pioglitazone also improved phenotypes impaired locomotion, DA neurodegeneration in rat PD model Rapamycin, an FDA-approved compound, induces autophagy by binding and inhibiting mTORC1 , and has been tested as a disease-modifying agent in experimental models of PD and neurodegenerative diseases It may downregulate intracellular ROS via Nrf2 pathway, glutathione and SOD , Nevertheless, it is also able to increase ROS levels, probably through c-Jun and endoplasmic reticulum ER stress pathway in certain circumstances Metformin, an mTOR inhibitor, activates mitophagy via signalling pathways including AMPK-Nrf2 as well as SIRT3 pathway , It has been shown to upregulate mitophagy in a recent randomized controlled clinical trial in type 2 diabetics Metformin has been found to downregulate ROS production , A longitudinal cohort study in an aging population with diabetes demonstrated a lower incidence of neurodegenerative diseases in those on long-term metformin therapy Of note, PD gene PARK9 encoded protein ATP13A2 is a lysosomal exporter of polyamine putrescine, spermidine, and spermine Spermine is pumped by ATP13A2 into the cytosol and subsequently absorbed by mitochondria.
The polyamine transport activity of ATP13A2 is responsible to counter the mitochondrial oxidative stress Mitochondrial defects observed in C. elegans carrying a mutation in CATP-6 a C. elegans ortholog of ATP13A2 was rescued via mitophagy induction In another study, spermidine was able to rescue behavioural deficits in the PD C.
Taken together, these studies suggest that spermidine may have neuroprotective effect on PD with ATPA being a key component.
Despite spermidine-generated ROS being a possible upstream signal in activating the latter ATM pathway , spermidine appears to act as direct ROS scavengers, resulting in inhibition of mitochondrial ROS production , Consistently, studies revealed neuroprotective effects of salidrosides in pre-clinical trials in Alzheimers disease, stroke and PD.
A number of these studies emphasized its safety and substantial bioactive effects on the regulation of oxidative stress Tomatidine, a natural compound with antiaging properties activates Nrf2-SKN-1 pathway, resulting in the C.
Tomatidine may activate mitophagy via Nrf2-SKN-1 pathway or TRAF6. Meanwhile, it may have a negligible or mild stimulating effect on ROS production , Honokiol, an agonist of SIRT3 known for anti-inflammatory and antitumor effects, promotes mitophagy and mitochondrial dynamics in vitro in an SIRT3-dependent manner via the AMPK-PGC-1α signalling pathway, and this neuroprotection has been validated in vivo It can augment Parkin expression, leading to Parkin-mediated mitophagy activation Similar observations of ROS inhibition by liraglutide has been consistently observed , Liraglutide shows good BBB permeability and neuroprotective effects in PD animal models We await the results of its ongoing trial in idiopathic PD, which should be completed soon.
gov Identifier: NCT As for the modulators of mitophagy reviewed elsewhere, most of the targets are localized on mitochondria , Therefore, modulation of these targets may have profound impacts on mitochondrial functions, including ROS homeostasis.
For instance, Ubiquitin-specific protease 30 USP30 removes ubiquin attached by Parkin to the OMM substrates, attenuating subsequent mitophagy. Based on its influence on mitophagy, USP30 inhibitors have been developed to promote mitophagy as a potential therapeutic option for PD , However, USP30 is also involved in the regulation of the import of intramitochondrial proteins, including subunits of electron transport chain proteins such as Complex-I Manipulation of USP30 may cause aberrant ROS generation by interfering the proper functions of the respiratory chain.
Thus, the effects of USP30 or other mitophagy regulators on ROS production have to be assessed and the benefit of neuroprotection through mitophagy and the potential detrimental effect of ROS dysregulation has to be weighed. Maximizing the potential therapeutic benefits of these compounds in Table 1 requires factoring in their effects on ROS levels.
Among them, a few compounds may potentially upregulate ROS, having a negative impact on cell survival. When applied in PD, these drugs should be coupled with ROS inhibitors general antioxidants or mitochondrial-targeted antioxidants necessary to negate any harmful oxidative effects.
Most compounds listed have apparently null effects or downregulate ROS levels, whereby their use in combination with ROS inhibitors may be considered to synergistically improve therapeutic performance We reason that mitophagy activation in PD relevant therapeutics should simultaneously avoid provoking oxidative stress, while maintaining their neuroprotective effects of downstream signalling on mitochondrial homeostasis, particularly mitochondrial turnover through autophagy-lysosomal pathway.
Some of these compounds are currently undergoing pre-clinical and clinical trials i. Liraglutide, Salidroside, and Melatonin in PD, further encouraging the efforts in drug repurposing.
Therapeutic usage of these compounds could implemented in a targeted manner or in combined multidrug regime with existing pharmacological carbidopa-levodopa, pramipexole etc and non-pharmacological approaches physical, occupational, speech therapies etc 6.
Drug repurposing, utilizing various degrees of pre-existing clinical efforts covering efficacy and safety efforts, offsets the high cost and lengthy timeline of de novo drug discovery However, drug repurposing comes with issues that should be taken into consideration, including but not limited to intellectual property considerations and high chance to fail in clinical trials , The ROS inhibitors as mentioned earlier creatine , vitamin E have yet to be proved as effective repurposing drugs in PD treatment.
Alternatively, potential therapeutic compounds for PD may be discovered de novo from the perspective of mitophagy. A recent study was conducted using an imaging-based drug screening in patient iPSC-derived neurons carrying Parkin or PINK1 mutation.
Among the compounds screened, 73 hits were found to promote mitophagy with two candidates attenuating ROS and cell death Large-scale screenings are needed to identify more potential compounds which can be further validated and taken to clinical trials. It should be noted that neurons are usually cultured in B27 supplemented neurobasal medium, which contains antioxidant to promote neuronal survival Potential oxidative stress caused by compounds may not be revealed in the cultured neurons.
Additionally, animal model may have different tolerance and compensative mechanism for mitophagy impairment 49 and ROS stress , Target-based screening with stringent validation of mitophagy activator may help to efficiently identify promising drug candidate.
The screening of mitophagy activator targeting ROS-related signalling pathways in the presence of certain antioxidant in mitophagy-intact or mitophagy-defective iPSC-derived neurons may yield compounds that potentially reverse the pathogenesis of PD.
The compounds identified in mitophagy-defective neurons represent the potential drug candidates which may promote alternative mitophagy to rescue PD caused by mitophagy defects. The candidates that can promote mitophagy in the presence of antioxidant may trigger mitophagy by activating certain signalling pathway while eliminating potential ROS-related detrimental effects.
With the efficient target-based screening, more efforts could be made to evaluate the effects of the hits on PD phenotypes in multiple model systems, including animal and human midbrain organoid PD model before taken into clinical trial together with the antioxidant Fig.
Alternatively, compound screening of mitophagy activator targeting ROS-related signalling pathways, may yield hits that potentially reverse the pathogenesis of PD. The hits of the screening should be validated in multiple PD model systems given the limitations of the current disease models.
The drug candidates identified from either strategy will be recommended to enter potential clinical trial with antioxidant therapy to aid removal of potential ROS-related detrimental effects. Therapeutic trials studying the potential of activating ROS downstream signalling pathway s to boost mitophagy face some challenges Table 2.
First, it is important to pinpoint mitophagy defects in relevant biological samples. In vitro culture of DA neurons or midbrain organoid derived from patient iPSCs may provide a useful tool to study mitophagy in vitro with the aid of constantly developing fluorescence dyes to readily detect mitophagy status or single cells sequencing to identify the cell populations and signalling pathways implicated in the mitophagy.
Furthermore, it is of note that pioglitazone failed to halt PD progression in trials, but lowered the risk of PD, suggesting that mitophagy activation in rescuing neurodegeneration is more likely to be useful in early stages of neurodegeneration, as opposed to clinically diagnosed PD patients whereby numerous cascades of cellular dysfunctions rendering neurodegeneration are inevitable and irreversible.
Hence clinical trials should focus on asymptomatic genetic carriers or those at risk or those with prodromic symptoms. A comprehensive analysis of genetic background known genes related to PD and longitudinal clinical studies of blood, urine and CSF biomarkers and clinical manifestation including symptoms of anosmia, REM disorder will help to stratify clinical trial subjects and to monitor their progression.
In conclusion, the dynamic and complex interplay between mitophagy and excessive ROS plays an important pathophysiologic role in both sporadic and familial PD. Identifying the relationship between these processes and their triggers early in the course of neurodegeneration will provide novel mechanistic clues that can potentially lead to the development of drugs that target specific pathways in this network.
Proper selection of specific subsets of subjects for longitudinal clinical trials will enhance the chance of a favourable therapeutic outcome. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
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Palacino, J. Mitochondrial Dysfunction and Oxidative Damage in parkin-deficient Mice. Piccoli, C. Mitochondrial respiratory dysfunction in familiar Parkinsonism associated with PINK1 mutation. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy.
Lin, Q. PINK1-parkin pathway of mitophagy protects against contrast-induced acute kidney injury via decreasing mitochondrial ROS and NLRP3 inflammasome activation.
Wang, B. AMPKa2 protects against the development of heart failure by enhancing mitophagy via PINK1 phosphorylation. Kong, H. Meade, R. Grünewald, A. Pink1 interacts with α-synuclein and abrogates α-synuclein-induced neurotoxicity by activating autophagy.
Di Maio, R. Ryan, S. Cannon, J. Ryan, T. Cardiolipin exposure on the outer mitochondrial membrane modulates α-synuclein. Taira, T. DJ-1 has a role in antioxidative stress to prevent cell death. Girotto, S. Dopamine-derived quinones affect the structure of the redox sensor DJ-1 through modifications at Cys and Cys Ryan, B.
Trends Biochem. Li, J. The role of the LRRK2 gene in Parkinsonism. Association of LRRK2 haplotype with age at onset in Parkinson disease.
JAMA Neurol. Nguyen, H. LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8 , — Thiol peroxidases ameliorate LRRK2 mutant-induced mitochondrial and dopaminergic neuronal degeneration in Drosophila. Accumulation of wild-type α-syn in DA neurons reduced mitochondrial complex I activity, elevated ROS production leading to cell death Martin et al.
It has been shown that α-syn inclusions elevate dendritic mitochondrial oxidative stress in DA neurons Dryanovski et al. This mitochondrial dysfunction occurs many months before the occurrence of striatal DA loss Subramaniam et al.
The nuclear translocation of α-syn increases susceptibility of MES Exposure to rotenone or other stimuli that promote ROS formation and mitochondrial alterations correlate well with mutant α-syn phosphorylation at Ser Perfeito et al.
Oxidative stress promotes uptake, accumulation, and oligomerization of extracellular α-syn in oligodendrocytes Pukass and Richter-Landsberg, and induces posttranslational modifications of α-syn which can increase DA toxicity Xiang et al. It has been suggested that the NADPH oxidases, which are responsible for ROS generation, could be major players in synucleinopathies Cristóvão et al.
DJ-1 is another gene reported to cause a familial early onset PD Puschmann, DJ-1 binds to subunits of mitochondrial complex I and regulates its activity Hayashi et al. Although a portion of DJ-1 is present in mitochondria matrix and inter-membrane space Zhang et al.
Mitochondrial-targeted sequence-conjugated DJ-1 has been shown to be more protective against oxidative stress-induced cell death Junn et al. DJ-1 KO mice displayed nigrostriatal DA neuron loss Goldberg et al. Also, these DJ-1 KO mice showed altered mitochondrial respiration and morphology, reduced membrane potential, and accumulation of defective mitochondria Irrcher et al.
These defects can be reversed by DJ-1 overexpression, which points to the specific role of DJ-1 in mitochondrial function Heo et al. Recently, following oxidative stress, DJ-1 was shown to be involved in the oxidative stress response that leads to the upregulation of the proteasome, thus inhibiting its activity and rescuing partially unfolded proteins from degradation Moscovitz et al.
Neuronal loss in PD is associated with chronic neuroinflammation, which is controlled primarily by microglia, the major resident immune cells in the brain Barcia et al.
Microglial activation has been found with a greater density in the SNpc Lawson et al. Additionally, activated microglia have been found in the SNpc and in the striatum of PD animal models Pisanu et al. In response to certain environmental toxins and endogenous proteins, microglia can shift to an over-activated state and release ROS which can cause neurotoxicity Block et al.
Accumulating evidence indicates that activation of different enzymes like NADPH oxidase NOX2 in microglia is neurotoxic not only through the production of extracellular ROS that damage neighboring neurons but also through the initiation of redox signaling in microglia that amplifies the pro-inflammatory response Surace and Block, Neuromelanin confers the dark pigmentation that is produced from DA oxidation and is so characteristic of the SNpc appearance.
High levels of catecholamine metabolism in the midbrain are associated with increased levels of neuromelanin in the same region and, it is neuromelanin that is thought to be one of the molecules responsible for inducing chronic neuroinflammation in PD. Neuromelanin released from dying DA neurons in the SNpc activate microglia, increasing the sensitivity of DA neurons to oxidative stress-mediated cell death Halliday et al.
The ability of neuromelanin to interact with transition metals, especially iron, and to mediate intracellular oxidative mechanisms have received particular attention.
Increased levels of iron result in increased ROS and increased oxidative stress and has been shown to be involved in aging and PD. Iron homeostasis is modulated by angiotensin in DA neurons and microglia, and glial cells play an essential role in the efficient regulation of this balance Garrido-Gil et al.
Dopamine neurons containing neuromelanin are especially more susceptible, indicating a possible role for neuromelanin in MPTP-toxicity Herrero et al. MPTP induces a glial response, increased levels of inflammatory cytokines and microglial activation in mice Członkowska et al.
Angiotensin is one of the most important inflammation and oxidative stress inducers, and produces ROS by activation of the NADPH-oxidase complex. It has been suggested that the inflammatory response in the MPTP model could be mediated by brain angiotensin and microglial NADPH-derived ROS Joglar et al.
Moreover, oral treatment with NADPH oxidase antagonists mitigates the clinical and pathological features of parkinsonism in the MPTP marmoset model Philippens et al. Also, microglia play an important role in mediating rotenone-induced neuronal degeneration through NADPH Gao et al.
Rotenone increased microglial activation in both the SNpc and striatum in rats Sherer et al. Extracellular α-syn released from neuronal cells is an endogenous agonist for Toll-like receptor 2 TLR2 , which activates the microglial inflammatory responses Kim et al.
An increased number of activated microglia and increased levels of TNF-α mRNA and protein were detected in the striatum and in the SNpc of mice over-expressing WT human α-syn Watson et al.
Moreover, in α-syn KO mice, microglia secreted higher levels of proinflammatory cytokines, TNF alpha and IL-6 interleukin-6 compared to WT mice Austin et al. Intracerebral injection of recombinant amyloidogenic or soluble α-syn induces extensive α-syn intracellular inclusion pathology that is associated with a robust gliosis Sacino et al.
LRRK2 increases proinflammatory cytokine release from activated primary microglial cells which results in neurotoxicity Gillardon et al. In contrast, LRRK2 inhibition attenuates microglial inflammatory responses Moehle et al.
Additionally, lipopolysaccharide induces LRRK2 up-regulation and microglial activation in mouse brains Li et al. Abnormal glial function is critical in parkin mutations, increasing vulnerability to inflammation-related nigral degeneration in PD Frank-Cannon et al. DJ-1 expression is up-regulated in reactive astrocytes in PD patients Bandopadhyay et al.
DJ-1 negatively regulates inflammatory responses of astrocytes and microglia by facilitating the interaction between STAT1 and its phosphatase SHP-1 Kim et al.
Astrocyte cultures from DJ-1 KO mice treated with lipopolysaccharide have increased NO production and an up-regulation of different pro-inflammatory mediators like COX-2 and IL-6 Waak et al.
The elements that potentially cause oxidative stress in PD are still unknown. DA metabolism, mitochondrial dysfunction and neuroinflammation all play critical roles in the etiology of this disease. Exposure to environmental factors or mutations in PD-associated genes of patients with either sporadic or familial PD may cause mitochondrial dysfunction that ultimately results in PD.
All of these share common linkages and influence each other greatly. Limiting the early inflammatory response will reduce further both elevated oxidative stress and microglial activation that are key to slowing the death of the neurons in the SNpc.
Development of potential drugs able to delay the neurodegenerative process is crucial to ameliorating the deleterious effects of oxidative stress in neurodegenerative diseases.
Neuroprotective therapies will need to target multiple pathological pathways such as mitochondrial dysfunction and neuroinflammation in the next few years. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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However, therapeutic attempts to target the general state of oxidative stress in clinical trials have failed to demonstrate an impact on disease progression. Recent knowledge gained about the specific mechanisms related to PD gene products that modulate ROS production and the response of neurons to stress may provide targeted new approaches towards neuroprotection.
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: Oxidative stress and Parkinsons disease| What is oxidative stress-induced Parkinsonism? | Vila Srress and Przedborski Wtress Targeting Kale for digestion cell death in neurodegenerative diseases. Pickrell, A. Portz, P. Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. Oral treatment with the NADPH oxidase antagonist apocynin mitigates clinical and pathological features of parkinsonism in the MPTP marmoset model. |
| Oxidative stress in Parkinson's disease | The CNS contains disase large Kale for digestion dixease mitochondria in anx to meet the demands of high oxidative stress and Parkinsons disease of Pariinsons consumption. PINK1 oxiative a mitochondrial High-protein snacks that is degraded rapidly Sports psychology and dietary habits healthy mitochondria. MPTP and SNpc DA neuronal Kale for digestion role anr dopamine, superoxide and nitric oxide oxidativr neurotoxicity. Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE. Ryan, T. These ROS attack all macromolecules, including lipids, proteins and nucleic acids, and trigger an inflammatory response, resulting in cellular damage, mitochondrial dysfunction, oxidative DNA injury and neuroinflammation, all of which have been considered as key contributors in the neurodegenerative process of PD 13 — This occurs possibly because it reduces the functioning of neuronal enzymes, since it is a cofactor of tyrosine hydroxylase and has a role in the synthesis of neurotransmitters. |
| Current Pharmaceutical Design | Neuromelanin in turn can exacerbate the neurodegenerative process by triggering neuroinflammation [ 20 ]. Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism. Restricted Access Panel ×. In fact, recent studies have confirmed damage to α-synuclein by lipids in PD individuals [ 54 ]. Neuronal loss in PD is associated with chronic neuroinflammation, which is controlled primarily by microglia, the resident innate immune cells and the main immune responsive cells in the central nervous system. Inhibition of DA production by α-methyl-p-tyrosine, a TH inhibitor, or antioxidant vitamin E reversed the α-synuclein overexpression-induced damage, supporting the hypothesis that DA fueled-oxidative stress plays a key role in mediating α-synuclein toxicity [ ]. |
| Oxidative stress and Parkinson’s disease | Cooking classes and workshops 38, — Rush JD and Koppenol WH: Oxivative intermediates in the Pwrkinsons of ferrous EDTA with hydrogen peroxide. Liu, T. Google Scholar Conway KA, Rochet JC, Bieganski RM, Lansbury Jr PT. Article CAS PubMed PubMed Central Google Scholar Veen, S. |
| COVID-19 and Oxidative Stress-Induced Parkinsonism | Mechanisms oxidatie functions Insulin resistance and gut health p38 MAPK signalling. When monomer, oligomer, or fibril forms of Kale for digestion oxiddative were added, α-synuclein oligomers triggered oxidative stress more potently than Parkijsons and oxidative stress and Parkinsons disease. Pisanu, A. ROS facilitate the Parkinssons of the mPTP, resulting diseaes neuronal apoptosis. This last scenario seems to involve PINK1 and Parkin in a common pathway that regulates mitochondrial physiology and cell survival in which PINK1 seems to be functioning upstream of Parkin, at least as observed in Drosophila disease models Clark et al. mt-Keima is a mitochondria-targeted fluorescent protein, which is sensitive to pH changes but resistant to degradation mediated by lysosomal proteases. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. |
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