Biology subjects

Ay, M.

Publications and source records attributed to Ay, M..

4 recordsLinked to original sources

bioRxiv2026

Paraquat Inhalation Produces Male-Biased Dopaminergic Neuron Loss and Motor Deficits in Mice: Relevance to Parkinsons Disease

Long-term exposure to paraquat (PQ), a widely used herbicide, has been linked to increased risk of Parkinsons 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 -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.

neuroscience↗

bioRxiv2025

Rationally Designed PKD1 Activator Protects Against Neurodegeneration in Pre-clinical Models of Parkinson's Disease

Oxidative stress leads to degeneration in Parkinsons disease (PD). The key signal transduction and regulatory networks that are involved during this degenerative process in PD are currently being investigated for novel neuro-protective strategies. We recently discovered that the activation of Protein Kinase D1 (PKD1) acts as a novel compensatory mechanism in PD models and positive modulation of PKD1 can be a therapeutic strategy. Therefore, the purpose of the present study was to take a translational approach by developing a PKD1 activator and characterizing the protective function in pre-clinical models of PD. Positive genetic modulation of PKD1 by overexpression of constitutively active PKD1 protected against MPP+ induced dopaminergic neurotoxicity. Pharmacological activation by Rosiglitazone protected, whereas inhibition by kb NB 142-70 exacerbated against MPP+ and 6-OHDA toxicity in cell culture PD models. Importantly, peptides were rationally designed and screened for their ability to activate PKD1 using our screening methods. Peptide AK-P4 was identified to activate PKD1 specifically and protect against MPP+ and 6-OHDA in both N27 cells and primary mesencephalic neurons. Further AK-P4 tagged with TAT sequence (AK-P4T) delivered using intra-venous injections activated PKD1 in mice. The neuro-protective effects of AK-P4T were tested using the sub-chronic MPTP mice model. Co-treatment with AK-P4T significantly restored the neurotransmitter levels and the behavioral and locomotory activities of the MPTP mouse model of PD. Collectively, our results demonstrate that rationally designed PKD1 activator peptide AK-P4T positively modulated PKD1 and protected against neurodegeneration in the pre-clinical models of PD. Our results suggest that positive modulation of the PKD1 using AK-P4T shows promise as a potential therapeutic agent against PD.

neuroscience↗

bioRxiv2020

Target-driven design of a coumarinyl chalcone scaffold based novel EF2 Kinase inhibitor suppresses breast cancer growth in vivo

Eukaryotic elongation factor 2 kinase (eEF-2K), an unusual alpha kinase, is involved in protein synthesis through phosphorylation of elongation factor 2 (EF2). eEF-2K is indicated as one of the critical drivers of breast cancer and associated with poor clinical prognosis, representing a potential molecular target. The crystal structure of eEF-2K is unknown and there is no potent and effective eEF-2K inhibitor reported for clinical applications. To meet this challenge, we designed and synthesized several generations of potential inhibitor compounds and performed in silico studies. The effect of the inhibitors at the binding pocket of eEF-2K is analyzed after developing a 3D target model by homology modeling approaches using a domain of another -kinase called myosin heavy-chain kinase A (MHCKA) that is closely resembling eEF-2K. Our results showed that compounds with coumarin-chalcone cores have a high predicted binding affinity for binding to eEF-2K. Following in vitro studies, we identified a compound that was highly effective in inhibiting eEF-2K activity at submicromolar concentrations and inhibited proliferation of various breast cancer cells with different features (BT20, MDA-MB-231, MDA-MB-436 and MCF-7) by induction of apoptosis while sparing normal cells. In vivo systemic administration of the the lead inhibitor encapsulated in single lipid-based nanoparticles twice a week significantly supressed growth of MDA-MB-231 tumors in orthotopic breast cancer models in nude mice. In conclusion, our study provides the first in vivo effective small molecule eEF-2K inhibitor that may be used for molecularly targeted precison medicine strategies in breast cancer or other eEF-2K-dependent tumors.

cancer biology↗

bioRxiv2020

Characterization of Nonmotor Symptoms in the MitoPark Mouse Model of Parkinson's Disease

Mitochondrial dysfunction has been implicated as a key player in the pathogenesis of Parkinsons 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 non-motor symptoms are now recognized as important features of the prodromal stage of PD, we monitored the clinically relevant motor and nonmotor symptoms from ages 8-24 wks in MitoPark mice and their littermate controls. As expected, motor deficits in MitoPark mice began around 12-14 wks and became severe by 16-24 wks. Interestingly, male MitoPark mice showed spatial memory deficits before female mice, beginning at 8 wks and becoming most severe at 16 wks, as determined by Morris water maze. When compared to age-matched control mice, MitoPark mice exhibited olfactory deficits in novel and social scent tests as early as 10-12 wks. MitoPark mice between 16-24 wks 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. Collectively, our results indicate that MitoPark mice progressively exhibit deficits in cognitive learning and memory, olfactory discrimination, and anxiety-and depression-like behaviors. Thus, MitoPark mice can serve as an invaluable model for studying motor and non-motor symptoms in addition to studying pathology in PD.

neuroscience↗