Etiology Of Parkinson's Disease Research Articles

Metabolic Basis of Circadian Dysfunction in Parkinson's Disease.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The management of PD is a challenging aspect for general physicians and neurologists. It is characterized by the progressive loss of dopaminergic neurons. Impaired α-synuclein secretion and dopamine release may cause mitochondrial dysfunction and perturb energy metabolism, subsequently altering the activity and survival of dopaminergic neurons, thus perpetuating the neurodegenerative process in PD. While the etiology of PD remains multifactorial, emerging research indicates a crucial role of circadian dysfunction in its pathogenesis. Researchers have revealed that circadian dysfunction and sleep disorders are common among PD subjects and disruption of circadian rhythms can increase the risk of PD. Hence, understanding the findings of circadian biology from translational research in PD is important for reducing the risk of neurodegeneration and for improving the quality of life. In this review, we discuss the intricate relationship between circadian dysfunction in cellular metabolism and PD by summarizing the evidence from animal models and human studies. Understanding the metabolic basis of circadian dysfunction in PD may shed light on novel therapeutic approaches to restore circadian rhythm, preserve dopaminergic function, and ameliorate disease progression. Further investigation into the complex interplay between circadian rhythm and PD pathogenesis is essential for the development of targeted therapies and interventions to alleviate the burden of this debilitating neurodegenerative disorder.

Alpha synuclein modulates mitochondrial Ca2+ uptake from ER during cell stimulation and under stress conditions

Alpha synuclein (a-syn) is an intrinsically disordered protein prevalent in neurons, and aggregated forms are associated with synucleinopathies including Parkinson’s disease (PD). Despite the biomedical importance and extensive studies, the physiological role of a-syn and its participation in etiology of PD remain uncertain. We showed previously in model RBL cells that a-syn colocalizes with mitochondrial membranes, depending on formation of N-terminal helices and increasing with mitochondrial stress1. We have now characterized this colocalization and functional correlates in RBL, HEK293, and N2a cells. We find that expression of a-syn enhances stimulated mitochondrial uptake of Ca2+ from the ER, depending on formation of its N-terminal helices but not on its disordered C-terminal tail. Our results are consistent with a-syn acting as a tether between mitochondria and ER, and we show increased contacts between these two organelles using structured illumination microscopy. We tested mitochondrial stress caused by toxins related to PD, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP/MPP+) and carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and found that a-syn prevents recovery of stimulated mitochondrial Ca2+ uptake. The C-terminal tail, and not N-terminal helices, is involved in this inhibitory activity, which is abrogated when phosphorylation site serine-129 is mutated (S129A). Correspondingly, we find that MPTP/MPP+ and CCCP stress is accompanied by both phosphorylation (pS129) and aggregation of a-syn. Overall, our results indicate that a-syn can participate as a tethering protein to modulate Ca2+ flux between ER and mitochondria, with potential physiological significance. A-syn can also prevent cellular recovery from toxin-induced mitochondrial dysfunction, which may represent a pathological role of a-syn in the etiology of PD.

Changes in smoking, alcohol consumption, and the risk of Parkinson's disease.

There have been no studies on the association between changes in smoking and alcohol consumption or combined changes in smoking and alcohol consumption frequencies and PD risk. To assess the influence of changes in smoking and alcohol consumption on the risk of Parkinson's disease (PD). National Health Insurance Service (NHIS) database between January 2009 to December 2011 was analyzed. A total of 3,931,741 patients were included. Study participants were followed up for the incidence of PD until December 2017. Compared to the sustained non-smokers, sustained light smokers (adjusted hazard ratio [aHR] 0.80, 95% confidence interval [CI] 0.75-0.85), sustained moderate smokers (aHR 0.54, 95% CI 0.47-0.61), and sustained heavy smokers (aHR 0.49, 95% CI 0.44-0.55) had a lower risk of PD. Compared to those who sustained non-drinking, sustained light drinkers (aHR 0.85 95% CI 0.89-0.91), sustained moderate drinkers (aHR 0.68, 95% CI 0.60-0.78), and sustained heavy drinkers (aHR 0.77, 95% CI 0.68-0.87) showed decreased risk of PD. Among non-drinkers, those who started drinking to a light level were at decreased risk of PD (aHR 0.84, 95% CI 0.77-0.91). Among non-smoking and non-drinking participants, those who initiated smoking only (aHR 0.78, 95% CI 0.70-0.86), drinking only (aHR 0.77, 95% CI 0.68-0.87), and both smoking and drinking (aHR 0.69, 95% CI 0.58-0.82) showed decreased risk of PD. Smoking is associated with decreased risk of PD with a dose-response relationship. Alcohol consumption at a light level may also be associated with decreased risk of PD. Further studies are warranted to find the possible mechanisms for the protective effects of smoking and drinking on PD, which may present insights into the etiology of PD.

Personalized Response of Parkinson's Disease Gut Microbiota to Nootropic Medicinal Herbs In Vitro: A Proof of Concept.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons. Although the etiology of PD remains elusive, it has been hypothesized that initial dysregulation may occur in the gastrointestinal tract and may be accompanied by gut barrier defects. A strong clinical interest in developing therapeutics exists, including for the treatment of gut microbiota and physiology. We previously reported the impact of healthy fecal microbiota anaerobic cultures supplemented with nootropic herbs. Here, we evaluated the effect of nootropic Ayurvedic herbs on fecal microbiota derived from subjects with PD in vitro using 16S rRNA sequencing. The microbiota underwent substantial change in response to each treatment, comparable in magnitude to that observed from healthy subjects. However, the fecal samples derived from each participant displayed unique changes, consistent with a personalized response. We used genome-wide metabolic reconstruction to predict the community's metabolic potential to produce products relevant to PD pathology, including SCFAs, vitamins and amino acid degradation products. These results suggest the potential value of conducting in vitro cultivation and analyses of PD stool samples as a means of prescreening patients to select the medicinal herbs for which that individual is most likely to respond and derive benefit.

Absolute quantification of neuromelanin in formalin-fixed human brains using absorbance spectrophotometry.

Parkinson's disease is characterised by a visual, preferential degeneration of the pigmented neurons in the substantia nigra. These neurons are pigmented by neuromelanin which decreases in Parkinson's disease. Not much is known about NM as it is difficult to study and quantify, primarily due to its insolubility in most solvents except alkali. Neuromelanin quantification could progress the development of biomarkers for prodromal Parkinson's disease and provide insights into the presently unclear role of neuromelanin in Parkinson's disease aetiology. Light microscopy with stereology can visualise pigmented neurons, but it cannot quantify neuromelanin concentrations. Absolute neuromelanin quantification using absorbance spectrophotometry is reported in the literature, but the methodology is dated and only works with fresh-frozen tissue. We have developed a quantification protocol to overcome these issues. The protocol involves breakdown of fixed tissue, dissolving the tissue neuromelanin in sodium hydroxide, and measuring the solution's 350 nm absorbance. Up to 100 brain samples can be analysed in parallel, using as little as 2 mg of tissue per sample. We used synthetic neuromelanin to construct the calibration curve rather than substantia nigra neuromelanin. Our protocol enzymatically synthesises neuromelanin from dopamine and L-cysteine followed by high-heat ageing. This protocol enables successful lysis of the fixed substantia nigra tissue and quantification in three brains, with neuromelanin concentrations ranging from 0.23-0.55 μg/mg tissue. Quantification was highly reproducible with an interassay coefficient of variation of 6.75% (n = 5). The absorbance spectra and elemental composition of the aged synthetic neuromelanin and substantia nigra neuromelanin show excellent overlap. Our protocol can robustly and reliably measure the absolute concentration of neuromelanin in formalin-fixed substantia nigra tissue. This will enable us to study how different factors affect neuromelanin and provide the basis for further development of Parkinson's disease biomarkers and further research into neuromelanin's role in the brain.

Nuclear DNA and Mitochondrial Damage of the Cooked Meat Carcinogen 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Human Neuroblastoma Cells.

Animal fat and iron-rich diets are risk factors for Parkinson's disease (PD). The heterocyclic aromatic amines (HAAs) harman and norharman are neurotoxicants formed in many foods and beverages, including cooked meats, suggesting a role for red meat in PD. The structurally related carcinogenic HAAs 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylmidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-9H-pyrido[2,3-b]indole (AαC) also form in cooked meats. We investigated the cytotoxicity, DNA-damaging potential, and mitochondrial damage of HAAs and their genotoxic HONH-HAA metabolites in galactose-dependent SH-SY5Y cells, a human neuroblastoma cell line relevant for PD-related neurotoxicity. All HAAs and HONH-HAAs induced weak toxicity except HONH-PhIP, which was 1000-fold more potent than the other chemicals. HONH-PhIP DNA adduct formation occurred at 300-fold higher levels than adducts formed with HONH-MeIQx and HONH-AαC, assuming similar cellular uptake rates. PhIP-DNA adduct levels occurred at concentrations as low as 1 nM and were threefold or higher and more persistent in mitochondrial DNA than nuclear DNA. N-Acetyltransferases (NATs), sulfotransferases, and kinases catalyzed PhIP-DNA binding and converted HONH-PhIP to highly reactive ester intermediates. DNA binding assays with cytosolic, mitochondrial, and nuclear fractions of SH-SY5Y fortified with cofactors revealed that cytosolic AcCoA-dependent enzymes, including NAT1, mainly carried out HONH-PhIP bioactivation to form N-acetoxy-PhIP, which binds to DNA. Furthermore, HONH-PHIP and N-acetoxy-PhIP inhibited mitochondrial complex-I, -II, and -III activities in isolated SH-SY5Y mitochondria. Mitochondrial respiratory chain complex dysfunction and DNA damage are major mechanisms in PD pathogenesis. Our data support the possible role of PhIP in PD etiology.

Lapatinib ditosylate rescues motor deficits in rotenone-intoxicated rats: Potential repurposing of anti-cancer drug as a disease-modifying agent in Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor deficits induced by dopaminergic neuronal death in the substantia nigra (SN). Finding a successful neuroprotective therapy is still challenging despite improved knowledge of the etiology of PD and a variety of medications intended to reduce symptoms. Lapatinib (LAP), an FDA-approved anti-cancer medication, has been stated to exert its effect through the modulation of oxidative stress. Furthermore, recent studies display the neuroprotective effects of LAP in epilepsy, encephalomyelitis, and Alzheimer's disease in rodent models through the modulation of oxidative stress and ferroptosis. Nevertheless, it is questionable whether LAP exerts neuroprotective effects in PD. In the current study, administration of 100 mg/kg LAP in rotenone-treated rats for 21 days ameliorates motor impairment, debilitated histopathological alterations, and revived dopaminergic neurons by increasing tyrosine hydroxylase (TH) expression in SN, along with increased dopamine level. LAP remarkably restored the antioxidant defense mechanism system, GPX4/GSH/NRF2 axis, inhibiting oxidative markers, including iron, TfR1, PTGS2, and 4-HNE, along with suppression of p-EGFR/c-SRC/PKCβII/PLC-γ/ACSL-4 pathway. Moreover, LAP modulates HSP90/CDC37 chaperone complex, regulating many key pathological markers of PD, including LRRK2, c-ABL, and α-syn. It is concluded that LAP has neuroprotective effects in PD via modulation of many key parameters implicated in PD pathogenesis. Taken together, the current study offers insights into the potential repositioning of LAP as a disease-modifying drug in PD.

Aflatoxin B1 Increases Soluble Epoxide Hydrolase in the Brain and Induces Neuroinflammation and Dopaminergic Neurotoxicity.

Parkinson's disease (PD) is an increasingly common neurodegenerative movement disorder with contributing factors that are still largely unexplored and currently no effective intervention strategy. Epidemiological and pre-clinical studies support the close association between environmental toxicant exposure and PD incidence. Aflatoxin B1 (AFB1), a hazardous mycotoxin commonly present in food and environment, is alarmingly high in many areas of the world. Previous evidence suggests that chronic exposure to AFB1 leads to neurological disorders as well as cancer. However, whether and how aflatoxin B1 contributes to the pathogenesis of PD is poorly understood. Here, oral exposure to AFB1 is shown to induce neuroinflammation, trigger the α-synuclein pathology, and cause dopaminergic neurotoxicity. This was accompanied by the increased expression and enzymatic activity of soluble epoxide hydrolase (sEH) in the mouse brain. Importantly, genetic deletion or pharmacological inhibition of sEH alleviated the AFB1-induced neuroinflammation by reducing microglia activation and suppressing pro-inflammatory factors in the brain. Furthermore, blocking the action of sEH attenuated dopaminergic neuron dysfunction caused by AFB1 in vivo and in vitro. Together, our findings suggest a contributing role of AFB1 to PD etiology and highlight sEH as a potential pharmacological target for alleviating PD-related neuronal disorders caused by AFB1 exposure.

Association of women-specific health factors in the severity of Parkinson’s disease

Parkinson’s disease (PD) is an age-related neurological disorder known for the observational differences in its risk, progression, and severity between men and women. While estrogen has been considered to be a protective factor in the development of PD, there is little known about the role that fluctuations in hormones and immune responses from sex-specific health experiences have in the disease’s development and severity. We sought to identify women-specific health experiences associated with PD severity, after adjusting for known PD factors, by developing and distributing a women-specific questionnaire across the United States and creating multivariable models for PD severity. We created a questionnaire that addresses women’s specific experiences and their PD clinical history and deployed it through The Parkinson’s Foundation: PD Generation. To determine the association between women-specific health factors and PD severity, we constructed multivariable logistic regression models based on the MDS-UPDRS scale and the participants’ questionnaire responses, genetics, and clinical data. For our initial launch in November 2021, we had 304 complete responses from PD GENEration. Univariate and multivariate logistic modeling found significant associations between major depressive disorder, perinatal depression, natural childbirth, LRRK2 genotype, B12 deficiency, total hysterectomy, and increased PD severity. This study is a nationally available questionnaire for women’s health and PD. It shifts the paradigm in understanding PD etiology and acknowledging how sex-specific experiences may contribute to PD severity. In addition, the work in this study sets the foundation for future research to investigate the factors behind sex differences in PD.

Microglia-specific knock-out of NF-κB/IKK2 increases the accumulation of misfolded α-synuclein through the inhibition of p62/sequestosome-1-dependent autophagy in the rotenone model of Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder worldwide, with a greater prevalence in men than women. The etiology of PD is largely unknown, although environmental exposures and neuroinflammation are linked to protein misfolding and disease progression. Activated microglia are known to promote neuroinflammation in PD, but how environmental agents interact with specific innate immune signaling pathways in microglia to stimulate conversion to a neurotoxic phenotype is not well understood. To determine how nuclear factor kappa B (NF-κB) signaling dynamics in microglia modulate neuroinflammation and dopaminergic neurodegeneration, we generated mice deficient in NF-κB activation in microglia (CX3CR1-Cre::IKK2fl/fl ) and exposed them to 2.5 mg/kg/day of rotenone for 14 days, followed by a 14-day post-lesioning incubation period. We postulated that inhibition of NF-κB signaling in microglia would reduce overall inflammatory injury in lesioned mice. Subsequent analysis indicated decreased expression of the NF-κB-regulated autophagy gene, sequestosome 1 (p62), in microglia, which is required for targeting ubiquitinated α-synuclein (α-syn) for lysosomal degradation. Knock-out animals had increased accumulation of misfolded α-syn within microglia, despite an overall reduction in neurodegeneration. Interestingly, this occurred more prominently in males. These data suggest that microglia play key biological roles in the degradation and clearance of misfolded α-syn and this process works in concert with the innate immune response associated with neuroinflammation. Importantly, the accumulation of misfolded α-syn protein aggregates alone did not increase neurodegeneration following exposure to rotenone but required the NF-κB-dependent inflammatory response in microglia.

Protective effects of cell permeable Tat-PIM2 protein on oxidative stress induced dopaminergic neuronal cell death

BackgroundOxidative stress is considered as one of the main causes of Parkinson's disease (PD), however the exact etiology of PD is still unknown. Although it is known that Proviral Integration Moloney-2 (PIM2) promotes cell survival by its ability to inhibit formation of reactive oxygen species (ROS) in the brain, the precise functional role of PIM2 in PD has not been fully studied yet. ObjectiveWe investigated the protective effect of PIM2 against apoptosis of dopaminergic neuronal cells caused by oxidative stress-induced ROS damage by using the cell permeable Tat-PIM2 fusion protein in vitro and in vivo. MethodsTransduction of Tat-PIM2 into SH-SY5Y cells and apoptotic signaling pathways were determined by Western blot analysis. Intracellular ROS production and DNA damage was confirmed by DCF-DA and TUNEL staining. Cell viability was determined by MTT assay. PD animal model was induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and protective effects were examined using immunohistochemistry. ResultsTransduced Tat-PIM2 inhibited the apoptotic caspase signaling and reduced the production of ROS induced by 1-methyl-4-phenylpyridinium (MPP+) in SH-SY5Y cells. Furthermore, we confirmed that Tat-PIM2 transduced into the substantia nigra (SN) region through the blood-brain barrier and this protein protected the Tyrosine hydroxylase-positive cells by observation of immunohistostaining. Tat-PIM2 also regulated antioxidant biomolecules such as SOD1, catalase, 4-HNE, and 8-OHdG which reduce the formation of ROS in the MPTP-induced PD mouse model. ConclusionThese results indicated that Tat-PIM2 markedly inhibited the loss of dopaminergic neurons by reducing ROS damage, suggesting that Tat-PIM2 might be a suitable therapeutic agent for PD.

Microglia and Astrocytes Dysfunction and Key Neuroinflammation-Based Biomarkers in Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease, with symptoms such as tremor, bradykinesia with rigidity, and depression appearing in the late stage of life. The key hallmark of PD is the loss or death of dopaminergic neurons in the region substantia nigra pars compacta. Neuroinflammation plays a key role in the etiology of PD, and the contribution of immunity-related events spurred the researchers to identify anti-inflammatory agents for the treatment of PD. Neuroinflammation-based biomarkers have been identified for diagnosing PD, and many cellular and animal models have been used to explain the underlying mechanism; however, the specific cause of neuroinflammation remains uncertain, and more research is underway. So far, microglia and astrocyte dysregulation has been reported in PD. Patients with PD develop neural toxicity, inflammation, and inclusion bodies due to activated microglia and a-synuclein-induced astrocyte conversion into A1 astrocytes. Major phenotypes of PD appear in the late stage of life, so there is a need to identify key early-stage biomarkers for proper management and diagnosis. Studies are under way to identify key neuroinflammation-based biomarkers for early detection of PD. This review uses a constructive analysis approach by studying and analyzing different research studies focused on the role of neuroinflammation in PD. The review summarizes microglia, astrocyte dysfunction, neuroinflammation, and key biomarkers in PD. An approach that incorporates multiple biomarkers could provide more reliable diagnosis of PD.

Metal Exposure and Risk of Parkinson Disease: A Systematic Review and Meta-Analysis.

Metal exposure has been suggested as a possible environmental risk factor for Parkinson disease (PD). We searched the PubMed, EMBASE, and Cochrane databases to systematically review the literature on the relationship between metal exposure and PD risk and to examine the overall quality of each study and the exposure assessment method. A total of 83 case-control studies and 5 cohort studies published duringthe period 1963-July 2021 were included, of which 73 were graded as being of low or moderate overall quality. Investigators in 69 studies adopted self-reported exposure and biomonitoring after disease diagnosis for exposure assessment approaches. The meta-analyses showed that concentrations of copper and iron in serum and concentrations of zinc in either serum or plasma were lower, while concentrations of magnesium in CSF and zinc in hair were higher, among PD cases as compared with controls. Cumulative lead levels in bone were found to be associated with increased risk of PD. We did not find associations between other metals and PD. The current level of evidence for associations between metals and PD risk is limited, as biases from methodological limitations cannot be ruled out. High-quality studies assessing metal levels before disease onset are needed to improve our understanding of the role of metals in the etiology of PD.

High-content phenotypic screen to identify small molecule enhancers of Parkin-dependent ubiquitination and mitophagy.

Mitochondrial dysfunction and aberrant mitochondrial homeostasis are key aspects of Parkinson's disease (PD) pathophysiology. Mutations in PINK1 and Parkin proteins lead to autosomal recessive PD, suggesting that defective mitochondrial clearance via mitophagy is key in PD etiology. Accelerating the identification and/or removal of dysfunctional mitochondria could therefore provide a disease-modifying approach to treatment. To that end, we performed a high-content phenotypic screen (HCS) of ∼125,000 small molecules to identify compounds that positively modulate mitochondrial accumulation of the PINK1-Parkin-dependent mitophagy initiation marker p-Ser65-Ub in Parkin haploinsufficiency (Parkin +/R275W) human fibroblasts. Following confirmatory counter-screening and orthogonal assays, we selected compounds of interest that enhance mitophagy-related biochemical and functional endpoints in patient-derived fibroblasts. Identification of inhibitors of the ubiquitin-specific peptidase and negative regulator of mitophagy USP30 within our hits further validated our approach. The compounds identified in this work provide a novel starting point for further investigation and optimization.

Mitochondrial Complex I as a Pathologic and Therapeutic Target for Parkinson's Disease.

The prevalence of Parkinson's disease (PD) continues to increase despite substantial research. Mounting evidence states that dysfunctional mitochondrial bioenergetics play a vital role in PD etiology. A disturbance in the electron transport chain, more precisely, disruption of the mitochondrial complex I (MCI), is the most detrimental factor. Due to increased susceptibility toward MCI damage, the dopaminergic neurons experience oxidative stress and a compromise in ATP production, leading to neurodegeneration and PD. This article reviews the association of MCI with pathological mechanisms like α-synucleinopathy, neuroinflammation, oxidative stress, and ER stress and also describes the potential therapeutic options explored to overcome MCI dysfunction and related consequences.

Infectious Microorganisms Seen as Etiologic Agents in Parkinson’s Disease

Infections represent a possible risk factor for parkinsonism and Parkinson's disease (PD) based on information from epidemiology and fundamental science. The risk is unclear for the majority of agents. Moreover, the latency between infection and PD seems to be very varied and often lengthy. In this review, the evidence supporting the potential involvement of infectious microorganisms in the development of Parkinson's disease is examined. Consequently, it is crucial to determine the cause and give additional treatment accordingly. Infection is an intriguing suggestion regarding the cause of Parkinson's disease. These findings demonstrate that persistent infection with viral and bacterial microorganisms might be a cause of Parkinson's disease. As an initiating factor, infection may generate a spectrum of gut microbiota dysbiosis, engagement of glial tissues, neuroinflammation, and alpha-synuclein accumulation, all of which may trigger and worsen the onset in Parkinson's disease also contribute to its progression. Still uncertain is the primary etiology of PD with infection. The possible pathophysiology of PD infection remains a matter of debate. Furthermore, additional study is required to determine if PD patients develop the disease due to infectious microorganisms or solely since they are more sensitive to infectious causes.

IN SILICO ANALYSIS OF THE POTENTIAL ROLE OF SRY GENE IN PARKINSON’S DISEASE

Amaç
 Parkinson hastalığı (PH) en sık görülen hareket hastalığıdır
 ve substansiya nigra bölgesindeki dopaminerjik
 nöronların kaybından kaynaklanmaktadır. PH’nin ilk
 motor semptomları ortaya çıkmaya başladığında dopaminerjik
 nöronların %60’ından fazlası zaten ölmüştür.
 PH’nin etiyolojisi tam olarak anlaşılmamış olsa
 da, PH’nin genetik ve çevresel faktörler arasındaki
 kompleks etkileşimler sonucu oluştuğuna inanılmaktadır.
 Önceki çalışmalar erkeklerin PH’ye yakalanma
 olasılığının kadınlara göre en az 1,5 kat daha fazla
 olduğunu göstermiştir. Bu çalışma, bir Y kromozomu
 geni olan SRY’nin PH’nin patogenezinde bir rol oynayıp
 oynamadığını in siliko yöntemlerle araştırmayı
 amaçlamıştır.
 Gereç ve Yöntem
 Farklı insan dokularındaki SRY mRNA ekspresyonu
 İnsan Protein Atlas (HPA)’yı kullanarak analiz edilmiştir.
 SRY ve PH ile ilişkili genler arasındaki etkileşimler
 STRING ve GeneMANIA veri tabanlarını kullanarak
 incelenmiştir. JASPAR veri tabanı, PH ile ilişkili bazı
 genlerin promotör bölgelerindeki muhtemel SRY bağlanma
 noktalarını belirlemek için kullanılmıştır. Son
 olarak, SRY ile etkileşim halindeki anahtar genleri belirlemek
 için BioGRID ve GeneMANIA veri tabanları
 kullanılmıştır.
 Bulgular
 İn siliko analizler PH ile ilişkili bazı genlerin promotör
 bölgelerinde SRY bağlanma noktası olduğunu ve SRY’nin
 androjen reseptör (AR) sinyalini düzenleyebileceğini
 ortaya çıkarmıştır.
 Sonuç
 Bu bulgular SRY’nin PH’nin patogenezinde rol oynayabileceğini
 ve bundan dolayı da PH’ye karşı yeni terapötik
 stratejiler geliştirmek için moleküler bir hedef
 vazifesi görebileceğini önermektedir.

Potassium Channels in Parkinson's Disease: Potential Roles in Its Pathogenesis and Innovative Molecular Targets for Treatment.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the midbrain. The loss of neurons results in a subsequent reduction of dopamine in the striatum, which underlies the core motor symptoms of PD. To date, there are no effective treatments to stop, slow, or reverse the pathologic progression of dopaminergic neurodegeneration. This unfortunate predicament is because of the current early stages in understanding the biologic targets and pathways involved in PD pathogenesis. Ion channels have become emerging targets for new therapeutic development for PD due to their essential roles in neuronal function and neuroinflammation. Potassium channels are the most prominent ion channel family and have been shown to be critically important in PD pathology because of their roles in modulating neuronal excitability, neurotransmitter release, synaptic transmission, and neuroinflammation. In this review, members of the subfamilies of voltage-gated K+ channels, inward rectifying K+ channels, and Ca2+-activated K+ channels are described. Evidence of the role of these channels in PD etiology is discussed together with the latest views on related pathologic mechanisms and their potential as biologic targets for developing neuroprotective drugs for PD. SIGNIFICANCE STATEMENT: Parkinson's disease (PD) is the second most common neurodegenerative disorder, featuring progressive degeneration of dopaminergic neurons in the midbrain. It is a multifactorial disease involving multiple risk factors and complex pathobiological mechanisms. Mounting evidence suggests that ion channels play vital roles in the pathogenesis and progression of PD by regulating neuronal excitability and immune cell function. Therefore, they have become "hot" biological targets for PD, as demonstrated by multiple clinical trials of drug candidates targeting ion channels for PD therapy.

Uncovering the Molecular Link Between Lead Toxicity and Parkinson's Disease.

Significance: Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects millions around the world. The etiology of PD remains unknown, but environmental and occupational exposures to heavy metals are likely at play, and may impact the severity of the disease. Lead is a toxin known to affect many organs in the body throughout life, particularly the central nervous system. Recent Advances: In this study, we summarize and examine the evidence for such environmental and/or occupational exposures, with a focus on the molecular mechanisms associated with lead exposure and its potential contribution to the onset of parkinsonism in PD. In particular, populational studies suggest higher bone and blood lead levels are associated with increased risk of PD. Interestingly, low levels of lead exposure in the very early stages of life cause increase the production of alpha-synuclein protein in animal models. Critical Issues: Although the specific mechanisms underlying this association have not been fully assessed, oxidative stress and mitochondrial dysfunction are likely implicated and may explain the toxic effects that connect lead exposure to parkinsonism. Future Directions: Additional pre-clinical and clinical studies should be performed in order to further document the molecular link between lead toxicity and PD, as this may open novel perspectives in terms of disease prevention. Antioxid. Redox Signal. 39, 321-335.

A novel splicing variant of DJ-1 in Parkinson's disease induces mitochondrial dysfunction

Several studies have identified mutations in neuroprotective genes in a few cases of Parkinson's disease (PD); however, the role of alternative splicing changes in PD remains unelucidated. Based on the transcriptome analysis of substantia nigra (SN) tissues obtained from PD cases and age-matched healthy controls, we identified a novel alternative splicing variant of DJ-1, lacking exon 6 (DJ-1ΔE6), frequently detected in the SN of patients with PD. We found that the exon 6 skipping of DJ-1 induces mitochondrial dysfunction and impaired antioxidant capability. According to an in silico modeling study, the exon 6 skipping of DJ-1 disrupts the structural state suitable for the oxidation of the cysteine 106 residue that is a prerequisite for activating its neuroprotective roles. Our results suggest that change in DJ-1 alternative splicing may contribute to PD progression and provide an insight for studying PD etiology and its potential therapeutic targets.