Biology subjects

Anantharam, V.

Publications and source records attributed to Anantharam, V..

8 recordsLinked to original sources

bioRxiv2025

Prokineticin-2 Upregulates GDNF in Astrocytes and Pharmacological Modulation of PK2 Receptors offers Neuroprotection in Experimental Models of Parkinson's Disease

Despite a wealth of preclinical studies establishing neuroprotective and neurorestorative properties of glial cell-line-derived neurotrophic factor (GDNF) in animal models of Parkinsons disease (PD), clinical trials utilizing direct intracranial infusion of GDNF protein, or adeno-associated virus (AAV)-mediated GDNF gene transfer has not achieved the desired efficacy, largely due to challenges in delivery methods. Given GDNFs strong potential for neuroprotection, alternative strategies to elevate its expression by beyond invasive injection or genetic manipulation remain a promising therapeutic avenue for PD. We previously reported that prokineticin signaling provides a compensatory protective response against dopaminergic neuronal degeneration in cell and animal models of PD. Herein, we report a novel finding that PK2 regulates GDNF gene expression in astrocytes, suggesting that PK2 signaling can be harnessed for neuroprotection in PD. Treatment of cultured astrocytes with the PK2 protein, PK2 gene overexpression or prokineticin receptor 1 (PKR1) agonist IS20 significantly induced the GDNF gene expression and the protein secretion, resulting in enhanced dopaminergic cell survival in cell culture models of PD. Importantly, systemic administration of IS20 through intraperitoneal or intranasal routes elevated GDNF levels in the mouse brain, including the nigrostriatal system. Furthermore, IS20 treatment conferred significant neuroprotective effects in both 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced and MitoPark transgenic mouse models of PD. Collectively, our translational findings suggest that pharmacological modulation PK2 signaling may unlock the full clinical benefit of GDNF, offering a novel and non-invasive therapeutic strategy for Parkinsons disease.

pharmacology and toxicology↗

bioRxiv2025

KCa3.1 Contributes to Neuroinflammation and Nigral Dopaminergic Neurodegeneration in Experimental models of Parkinson's Disease

Chronic neuroinflammation and misfolded -synuclein (Syn) have been identified as key pathological correlates driving Parkinsons disease (PD) pathogenesis; however, the contribution of ion channels to microglia activation in the context of -synucleinopathy remains elusive. Herein, we show that KCa3.1, a calcium-activated potassium channel, is robustly upregulated within microglia in multiple preclinical models of PD and, most importantly, in human PD and dementia with Lewy bodies (DLB) brains. Pharmacological inhibition of KCa3.1 via senicapoc or TRAM-34 inhibits KCa3.1 channel activity and the associated reactive microglial phenotype in response to aggregated Syn, as well as ameliorates of PD like pathology in diverse PD mouse models. Additionally, proteomic and transcriptomic profiling of microglia revealed that senicapoc ameliorates aggregated Syn-induced, inflammation-associated pathways and dysregulated metabolism in primary microglial cells. Mechanistically, FYN kinase in a STAT1 dependent manner regulates KCa3.1 mediated the microglial reactive activation phenotype after -synucleinopathy. Moreover, reduced neuroinflammation and subsequent PD-like neuropathology were observed in SYN AAV inoculated KCa3.1 knockout mice. Together, these findings suggest that KCa3.1 inhibition represents a novel therapeutic strategy for treating patients with PD and related -synucleinopathies.

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↗

bioRxiv2024

Mitochondrial dysfunction Impairs the Nuclear Pore Complex in Parkinson's Disease Pathogenesis

The mislocalization of transcription factors and irregularities in the nuclear envelope of dopaminergic neurons affected by Parkinsons disease (PD) implicates the nuclear pore in disease pathogenesis. While mitochondrial dysfunction is an integral component of PD pathophysiology, the involvement of channel-forming nucleoporins (Nups) in mitochondrial dysfunction-related neurodegeneration has not been investigated. Here we have identified pathological changes in the levels and distribution of a set of Nups, which are key structural and functional components of the nuclear pore complex, in dopaminergic neuronal models of PD. We observed that mitochondrial dysfunction reduces the expression of these Nups and disrupts the localization of Ran GTPase in both in vitro and in vivo dopaminergic neuron models. Furthermore, the nuclear pore central channel component, Nup62, mislocalizes and accumulates in the cytoplasm of these neurons under mitochondrial stress conditions. Mitochondrial stress also interferes with classical nuclear export of proteins in dopaminergic neural cells. Notably, we observed Nup pathology and Ran gradient loss in nigral dopaminergic neurons of PD patient brains, which highlights the clinical relevance of nuclear pore dysfunction as a disease mechanism. These findings provide direct evidence of the critical role of Nup-related abnormalities in mitochondrial dysfunction-induced degeneration of dopaminergic neurons, ultimately connecting nuclear pore complex and nucleocytoplasmic transport dysregulation to cell death in the development of PD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=158 HEIGHT=200 SRC="FIGDIR/small/622143v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@193d8acorg.highwire.dtl.DTLVardef@176135forg.highwire.dtl.DTLVardef@f1edceorg.highwire.dtl.DTLVardef@1338d9d_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Epitranscriptomic Reader YTHDF2 Regulates SEK1(MAP2K4)-JNK-cJUN Inflammatory Signaling in Astrocytes during Neurotoxic Stress

As the most abundant glial cells in the CNS, astrocytes dynamically respond to neurotoxic stress, however, the key molecular regulators controlling the inflammatory status of these sentinels during neurotoxic stress have remained elusive. Herein, we demonstrate that the m6A epitranscriptomic mRNA modification tightly regulates the pro-inflammatory functions of astrocytes. Specifically, the astrocytic neurotoxic stresser, manganese (Mn), downregulated the m6A reader YTHDF2 in human and mouse astrocyte cultures and in the mouse brain. Functionally, YTHDF2 knockdown augmented, while its overexpression dampened, neurotoxic stress induced proinflammatory response, suggesting YTHDF2 serves as a key upstream regulator of inflammatory responses in astrocytes. Mechnistically, YTHDF2 RIP-sequencing identified MAP2K4 (MKK4; SEK1) mRNA as a YTHDF2 target influencing inflammatory signaling. Our target validation revealed Mn-exposed astrocytes mediates proinflammatory response by activating the phosphorylation of SEK1, JNK, and cJUN signaling. Collectively, YTHDF2 serves a key upstream molecular switch controlling SEK1(MAP2K4)-JNK-cJUN proinflammatory signaling in astrocytes.

neuroscience↗

bioRxiv2021

Clostridioides difficile infection increases circulating p-cresol levels and dysregulates brain dopamine metabolism: linking gut-brain axis to autism and other neurologic disorders?

Gastrointestinal illnesses are one of the most common comorbidities reported in patients with neurodevelopmental diseases, including autism spectrum disorders (ASD). Gut dysbiosis, overgrowth of C. difficile, and gut microbiota-associated alterations in central neurotransmission have been implicated in ASD, where the dopaminergic axis plays an important role in the disease pathogenesis. Human C. difficile strains produce a significant amount of the toxic metabolite p-cresol, an inhibitor of dopamine beta-hydroxylase (DBH), which catalyzes the conversion of dopamine (DA) to norepinephrine (NE). p-Cresol is known to precipitate and exacerbate autistic behavior in rodents by increasing DA levels and altering DA receptor sensitivity in brain regions relevant to ASD. Therefore, we hypothesized that C. difficile infection dysregulates dopaminergic metabolism by increasing p-cresol levels in the gut and systemic circulation, and by inhibiting brain DBH, ultimately leading to elevated DA in different brain regions. For testing this hypothesis, we induced antibiotic-associated C. difficile infection in mice and determined the gut and serum p-cresol levels, serum DBH activity, and dopamine and its metabolite levels in different brain regions relevant to ASD. The results showed that C. difficile infection causes a significant increase in striatal DA, accompanied by significantly altered levels of DA metabolites and NE in different brain regions (p < 0.05). In addition, significantly increased circulating p-cresol levels and reduced DBH activity were observed in C. difficile infected mice (p < 0.05). Therefore, the results from this study suggest a potential link between C. difficile infection and alterations in the dopaminergic axis implicated in the precipitation and aggravation of ASD.

neuroscience↗

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↗

bioRxiv2019

Mitochondrial Dysfunction Induces Epigenetic Dysregulation by H3K27 Hyperacetylation to Perturb Active Enhancers in Parkinson’s Disease Models

Genetic mutations explain only 10-15% of cases of Parkinsons disease (PD), while an overriding environmental component has been implicated in the etiopathogenesis of PD. But regardless of where the underlying triggers for the onset of familial and sporadic PD fall on the gene-environment axis, mitochondrial dysfunction emerges as a common mediator of dopaminergic neuronal degeneration. Herein, we employ a multidisciplinary approach to convincingly demonstrate that neurotoxicant exposure- and genetic mutation-driven mitochondrial dysfunction share a common mechanism of epigenetic dysregulation. Under both scenarios, lysine 27 acetylation of likely variant H3.2 (H3.2K27ac) increased in dopaminergic neuronal models of PD, thereby opening that region to active enhancer activity via H3K27 hyperacetylation. These vulnerable epigenomic loci represent potential transcription factor motifs for PD pathogenesis. We further confirmed the mitochondrial dysfunction induced H3K27ac during neurodegeneration in ex vivo models of PD. Our results reveal an exciting axis of exposure/mutation-mitochondrial dysfunction-metabolism-H3K27ac-transcriptome for PD pathogenesis. Collectively, the novel mechanistic insights presented here interlinks mitochondrial dysfunction to epigenetic transcriptional regulation in dopaminergic degeneration as well as offer potential new epigenetic intervention strategies for PD.

neuroscience↗