Muhammet Ay

Long-term exposure to paraquat (PQ), a widely used herbicide, has been linked to increased risk of Parkinson’s Disease (PD) in agricultural workers and rural communities in the United States (US), findings further supported by experimental animal studies. Although banned in many countries across the globe, PQ remains widely used in the US. Inhalation of PQ has been known to induce systemic organ failure at acute concentrations. However, prolonged low-dose inhalation from agricultural spraying and pesticide drift has not been readily evaluated for its potential to contribute to neurodegenerative diseases in vivo . Instead, many experimental studies have relied on systemic routes of exposure, which do not effectively replicate the most common route of exposure to PQ in the environment. In the current study, Parkinsonian features were examined in mice that had been exposed via whole-body inhalation to PQ aerosol for either 40 or 60 days. Levels of PQ in brain were highest in olfactory bulb, followed by frontal cortex and then brainstem in both sexes. After 60 days of exposure, male-specific impairments in locomotor activity were observed, in addition to reductions in striatal dopamine, in substantia nigra tyrosine hydroxylase (TH) expression and number of TH+ dopaminergic neurons, the latter being considered the primary basis of PD, along with increased olfactory bulb α-synuclein levels. As such, these studies confirm the dopaminergic neurotoxicity of inhaled PQ. These findings raise significant concerns as to the contribution of PQ exposures to the continued increase in the incidence of PD in the US. One-sentence summary: Paraquat inhalation in mice induces male-biased dopaminergic neuron loss and motor function deficits coupled with increased levels of α-synuclein.

Significant progress has been made over the past decade in measuring the chemical components of the exposome, providing transformative population-scale frameworks in probing the etiologic link between environmental factors and disease phenotypes. While the analytical technologies continue to evolve with reams of data being generated, there is an opportunity to complement exposome-wide association studies (ExWAS) with functional analyses to advance etiologic search at organismal, cellular, and molecular levels. Exposomics is a transdisciplinary field aimed at enabling discovery-based analysis of the nongenetic factors that contribute to disease, including numerous environmental chemical stressors. While advances in exposure assessment are enhancing population-based discovery of exposome-wide effects and chemical exposure agents, functional screening and elucidation of biological effects of exposures represent the next logical step toward precision environmental health and medicine. In this work, we focus on the use, strategies, and prospects of alternative approaches and model systems to enhance the current human exposomics framework in biomarker search and causal understanding, spanning from bench-based nonmammalian organisms and cell culture to computational new approach methods (NAMs). We visit the definition of the functional exposome and exposomics and discuss a need to leverage alternative models as opposed to mammalian animals for delineating exposome-wide health effects. Under the "three Rs" principle of reduction, replacement, and refinement, model systems such as roundworms, fruit flies, zebrafish, and induced pluripotent stem cells (iPSCs) are advantageous over mammals (e.g., rodents or higher vertebrates). These models are cost-effective, and cell-specific genetic manipulations in these models are easier and faster, compared to mammalian models. Meanwhile, in silico NAMs enhance hazard identification and risk assessment in humans by bridging the translational gaps between toxicology data and etiologic inference, as represented by in vitro to in vivo extrapolation (IVIVE) and integrated approaches to testing and assessment (IATA) under the adverse outcome pathway (AOP) framework. Together, these alternatives offer a strong toolbox to support functional exposomics to study toxicity and causal mediators underpinning exposure-disease links. https://doi.org/10.1289/EHP13120.

Increasing evidence implicates impaired mitochondrial biogenesis as an important contributor to mitochondrial dysfunction, which plays a central role in the pathogenesis of neurodegenerative diseases including Parkinson’s disease (PD). For this reason, targeting mitochondrial biogenesis may present a promising therapeutic strategy for PD. The present study attempted to investigate the effects of fisetin, a dietary flavonoid, on mitochondrial biogenesis and the expression of PD-associated genes in neuronal cells. The effects of fisetin on mitochondrial biogenesis were evaluated by three different approaches; PGC-1α and TFAM mRNA expressions by RT-qPCR, mitochondrial DNA (mtDNA) content by quantitative PCR and mitochondrial mass by MitoTracker staining. Next, a PCR array was performed to evaluate the effects of fisetin on the expression profile of PD-associated genes. Finally, the common targets of fisetin and PD were analyzed by in silico analyses. The results demonstrated that fisetin treatment can increase PGC-1α and TFAM mRNA levels, mtDNA copy number, and mitochondrial mass in neuronal cells. Fisetin also altered the expressions of some PD-related genes involved in neuroprotection and neuronal differentiation. Moreover, the bioinformatics analyses suggested that the AKT1-GSK3B signaling might be responsible for the potential neuroprotective effects of fisetin. Collectively, these results imply that fisetin could modulate some neuroprotective mechanisms including mitochondrial biogenesis, and may serve as a potential drug candidate for PD.

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.

Background Mitochondrial dysfunction has been recognized as an important mechanism of neurodegeneration. Accumulating evidence now suggests that defects in mitochondrial biogenesis can cause mitochondrial dysfunction in neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Therefore, identifying small molecules that can stimulate mitochondrial biogenesis may represent a therapeutic strategy for neuroprotection. The aim of this study was to investigate the effects of a natural compound vanillic acid (VA) on mitochondrial biogenesis and the expression of PD-related genes in SH-SY5Y cells. Methods and Results After determining the IC50 and non-toxic concentrations of VA, SH-SY5Y cells were exposed to a non-toxic dose of VA (300 µM) for 18 h. VA treatment resulted in significant increases in the mRNA expressions of mitochondrial biogenesis markers, PGC-1α and TFAM. Moreover, treatment of SH-SY5Y cells with 300 µM VA for 24 h significantly elevated the mitochondrial DNA (mtDNA) copy number and mitochondrial mass. Furthermore, the effects of VA on the expression of PD-related genes were analyzed using a real-time PCR array. The PCR array analysis revealed that VA can induce the expression of some genes involved in neuronal differentiation and also affect the expression of two PARK genes, PARK2 and LRRK2, whose mutations cause familial PD. Conclusions Together, these findings indicate that VA could serve as a potential neuroprotective agent by virtue of its ability to stimulate mitochondrial biogenesis in neuronal cells and to alter the expression of some genes related to the pathogenesis of PD and neuronal differentiation.

Characterization of the key cellular targets contributing to sustained microglial activation in neurodegenerative diseases, including Parkinson’s disease (PD), and optimal modulation of these targets can provide potential treatments to halt disease progression. Here, we demonstrated that microglial Kv1.3, a voltage-gated potassium channel, was transcriptionally upregulated in response to aggregated α-synuclein (αSyn_Agg) stimulation in primary microglial cultures and animal models of PD, as well as in postmortem human PD brains. Patch-clamp electrophysiological studies confirmed that the observed Kv1.3 upregulation translated to increased Kv1.3 channel activity. The kinase Fyn, a risk factor for PD, modulated transcriptional upregulation and posttranslational modification of microglial Kv1.3. Multiple state-of-the-art analyses, including Duolink proximity ligation assay imaging, revealed that Fyn directly bound to Kv1.3 and posttranslationally modified its channel activity. Furthermore, we demonstrated the functional relevance of Kv1.3 in augmenting the neuroinflammatory response by using Kv1.3-KO primary microglia and the Kv1.3-specific small-molecule inhibitor PAP-1, thus highlighting the importance of Kv1.3 in neuroinflammation. Administration of PAP-1 significantly inhibited neurodegeneration and neuroinflammation in multiple animal models of PD. Collectively, our results imply that Fyn-dependent regulation of Kv1.3 channels plays an obligatory role in accentuating the neuroinflammatory response in PD and identify Kv1.3 as a potential therapeutic target for PD.

Aims: Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive motor deficits and degeneration of dopaminergic neurons. Caused by a number of genetic and environmental factors, mitochondrial dysfunction and oxidative stress play a role in neurodegeneration in PD. By selectively knocking out mitochondrial transcription factor A (TFAM) in dopaminergic neurons, the transgenic MitoPark mice recapitulate many signature features of the disease, including progressive motor deficits, neuronal loss, and protein inclusions. In the present study, we evaluated the neuroprotective efficacy of a novel mitochondrially targeted antioxidant, Mito-apocynin, in MitoPark mice and cell culture models of neuroinflammation and mitochondrial dysfunction. Results: Oral administration of Mito-apocynin (10 mg/kg, thrice a week) showed excellent central nervous system bioavailability and significantly improved locomotor activity and coordination in MitoPark mice. Importantly, Mito-apocynin also partially attenuated severe nigrostriatal degeneration in MitoPark mice. Mechanistic studies revealed that Mito-apo improves mitochondrial function and inhibits NOX2 activation, oxidative damage, and neuroinflammation. Innovation: The properties of Mito-apocynin identified in the MitoPark transgenic mouse model strongly support potential clinical applications for Mito-apocynin as a viable neuroprotective and anti-neuroinflammatory drug for treating PD when compared to conventional therapeutic approaches. Conclusion: Collectively, our data demonstrate, for the first time, that a novel orally active apocynin derivative improves behavioral, inflammatory, and neurodegenerative processes in a severe progressive dopaminergic neurodegenerative model of PD. Antioxid. Redox Signal. 27, 1048–1066.

Vanadium (V) is a transition metal that presents in multiple oxidation states and numerous inorganic compounds and is also an ultra-trace element considered to be essential for most living organisms. Despite being one of the lightest metals, V offers high structural strength and good corrosion resistance and thus has been widely adopted for high-strength steel manufacturing. High doses of V exposure are toxic, and inhalation exposure to V adversely affects the respiratory system. The neurotoxicological properties of V are just beginning to be identified. Recent studies by our group and others demonstrate the neurotoxic potential of this metal in the nigrostriatal system and other parts of the central nervous system (CNS). The neurotoxic effects of V have been mainly attributed to its ability to induce the generation of reactive oxygen species (ROS). It is noteworthy that the neurotoxicity induced by occupational V exposure commonly occurs with co-exposure to other metals, especially manganese (Mn). This review focuses on the chemistry, pharmacology, toxicology, and neurotoxicity of V.