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    Characterization of nonmotor behavioral impairments and their neurochemical mechanisms in the MitoPark mouse model of progressive neurodegeneration in Parkinson's disease
    (Academic Press Inc Elsevier Science, 2021) Langley, Monica R.; Ghaisas, Shivani; Palanisamy, Bharathi N.; Ay, Muhammet; Jin, Huajun; Anantharam, Vellareddy; Kanthasamy, Arthi
    Mitochondrial dysfunction has been implicated as a key player in the pathogenesis of Parkinson's disease (PD). The MitoPark mouse, a transgenic mitochondrial impairment model developed by specific inactivation of TFAM in dopaminergic neurons, spontaneously exhibits progressive motor deficits and neurodegeneration, recapitulating several features of PD. Since nonmotor symptoms are now recognized as important features of the prodromal stage of PD, we comprehensively assessed the clinically relevant motor and nonmotor deficiencies from ages 8-24 wk in both male and female MitoPark mice and their littermate controls. As expected, motor deficits in MitoPark mice began around 12-14 wk and became severe by 16-24 wk. Interestingly, MitoPark mice exhibited olfactory deficits in the novel and social scent tests as early as 10-12 wk as compared to age-matched littermate controls. Additionally, male MitoPark mice showed spatial memory deficits before female mice, beginning at 8 wk and becoming most severe at 16 wk, as determined by the Morris water maze. MitoPark mice between 16 and 24 wk spent more time immobile in forced swim and tail suspension tests, and made fewer entries into open arms of the elevated plus maze, indicating a depressive and anxiety-like phenotype, respectively. Importantly, depressive behavior as determined by immobility in forced swim test was reversible by antidepressant treatment with desipramine. Neurochemical and mechanistic studies revealed significant changes in CREB phosphorylation, BDNF, and catecholamine levels as well as neurogenesis in key brain regions. Collectively, our results indicate that MitoPark mice progressively exhibit deficits in olfactory discrimination, cognitive learning and memory, and anxiety- and depression-like behaviors as well as key neurochemical signaling associated with nonmotor deficits in PD. Thus, MitoPark mice can serve as an invaluable model for studying nonmotor deficits in addition to studying the motor deficits related to pathology in PD.
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    Evaluation of fisetin as a potential inducer of mitochondrial biogenesis in SH-SY5Y neuronal cells
    (Mashhad Univ Med Sciences, 2023) Ay, Muhammet
    Objective(s): 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. Materials and Methods: The effects of fisetin on mitochondrial biogenesis were evaluated by three different approaches; PGC-1 alpha 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. Results: The results demonstrated that fisetin treatment can increase PGC-1 alpha 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. Conclusion: Collectively, these results imply that fisetin could modulate some neuroprotective mechanisms including mitochondrial biogenesis, and may serve as a potential drug candidate for PD.
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    Mito-metformin protects against mitochondrial dysfunction and dopaminergic neuronal degeneration by activating upstream PKD1 signaling in cell culture and MitoPark animal models of Parkinson’s disease
    (Frontiers Media SA, 2024) Ay, Muhammet; Charli, Adhithiya; Langley, Monica R.; Jang, Ahyoung; Padhi, Piyush; Jin, Huajun; Anantharam, Vellareddy
    Impaired mitochondrial function and biogenesis have strongly been implicated in the pathogenesis of Parkinson’s disease (PD). Thus, identifying the key signaling mechanisms regulating mitochondrial biogenesis is crucial to developing new treatment strategies for PD. We previously reported that protein kinase D1 (PKD1) activation protects against neuronal cell death in PD models by regulating mitochondrial biogenesis. To further harness the translational drug discovery potential of targeting PKD1-mediated neuroprotective signaling, we synthesized mito-metformin (Mito-Met), a mitochondria-targeted analog derived from conjugating the anti-diabetic drug metformin with a triphenylphosphonium functional group, and then evaluated the preclinical efficacy of Mito-Met in cell culture and MitoPark animal models of PD. Mito-Met (100–300 nM) significantly activated PKD1 phosphorylation, as well as downstream Akt and AMPK? phosphorylation, more potently than metformin, in N27 dopaminergic neuronal cells. Furthermore, treatment with Mito-Met upregulated the mRNA and protein expression of mitochondrial transcription factor A (TFAM) implying that Mito-Met can promote mitochondrial biogenesis. Interestingly, Mito-Met significantly increased mitochondrial bioenergetics capacity in N27 dopaminergic cells. Mito-Met also reduced mitochondrial fragmentation induced by the Parkinsonian neurotoxicant MPP+ in N27 cells and protected against MPP+-induced TH-positive neurite loss in primary neurons. More importantly, Mito-Met treatment (10 mg/kg, oral gavage for 8 week) significantly improved motor deficits and reduced striatal dopamine depletion in MitoPark mice. Taken together, our results demonstrate that Mito-Met possesses profound neuroprotective effects in both in vitro and in vivo models of PD, suggesting that pharmacological activation of PKD1 signaling could be a novel neuroprotective translational strategy in PD and other related neurocognitive diseases. © © 2024 Ay, Charli, Langley, Jang, Padhi, Jin, Anantharam, Kalyanaraman, Kanthasamy and Kanthasamy.
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    SRY GENİNİN PARKİNSON HASTALIĞINDAKİ POTANSİYEL ROLÜNÜN İN SİLİKO ANALİZİ
    (2023) Ay, Muhammet
    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.
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    Vanillic acid induces mitochondrial biogenesis in SH-SY5Y cells
    (Springer, 2022) Ay, Muhammet
    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 mu M) for 18 h. VA treatment resulted in significant increases in the mRNA expressions of mitochondrial biogenesis markers, PGC-1 alpha and TFAM. Moreover, treatment of SH-SY5Y cells with 300 mu M 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.