Biology subjects

Kanthasamy, A.

Publications and source records attributed to Kanthasamy, A..

13 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↗

bioRxiv2025

Exploring the Role of Kv1.3 and MAPK14 in Mediating Microglial Oxidative Stress and Neuroinflammation Following Organic Dust Exposure

BackgroundAgricultural contaminants, including inhaled organic dust (OD) and gases, are known to cause inflammation in the lungs and the brain. We investigated the role of the potassium channel Kv1.3 in organic dust (OD)-induced neuroinflammation models. Kv1.3 channels play a multifaceted role in microglial immune modulation, cancer, neurodegenerative diseases, and constitute a potential therapeutic target. MethodsWe used in vivo (C57BL/6 mice), in vitro (microglial cell line, primary microglia), and ex vivo (brain slice culture) models of OD-induced neuroinflammation. A sterile OD extract (ODE) was prepared, and mice were exposed to either normal saline or ODE intra-nasally for 5 weeks (5 days/week) to simulate an occupational exposure scenario. Primary microglia were isolated from neonatal mice for total RNA sequencing (RNA-seq). The ODE-induced expression of Kv1.3 was quantified using in vitro and ex vivo models with and without PAP-1 treatments. Exposure-induced changes in cytokines and reactive species markers were measured. Using western blot, we quantified phosphorylated p38 MAPK14 (p-p38 MAPK) and NOX2. We measured the currents through Kv1.3 channels using a microglial patch-clamp assay. ResultsExposure to ODE increased the expression of Kv1.3 and p-p38 MAPK in mouse microglia without affecting the Kv1.3 currents at the cell surface. Exposure increased the levels of inflammatory cytokines and NOX2. Kv1.3 inhibition with PAP-1 decreased inflammatory markers (TNF- and IL-6), levels of Kv1.3, p-p38 MAPK, NOX2, and nitrites. ConclusionOur study revealed that pharmacological inhibition of Kv1.3 potassium channels reduces ODE-induced neuroinflammation by decreasing inflammatory and oxidative stress markers.

pharmacology and toxicology↗

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

Mitochondrial Stress Disassembles Nuclear Architecture through Proteolytic Activation of PKCδ and Lamin B1 Phosphorylation in Neuronal Cells: Implications for Pathogenesis of Age-related Neurodegenerative Diseases

Mitochondrial dysfunction and oxidative stress are hallmarks of pathophysiological processes in age-related neurodegenerative diseases including Parkinsons, Alzheimers and Huntingtons diseases. Neuronal cells are highly vulnerable to mitochondrial stress, however, the cellular and molecular mechanisms underlying the enhanced vulnerability are not well understood. Previously, we demonstrated that the novel PKC isoform PKC{delta} is highly expressed in dopamin(DA)ergic neurons and plays a key role in inducing apoptotic cell death during neurotoxic stress via caspase-3-mediated proteolytic activation. Herein, we further uncovered a key downstream molecular event of PKC{delta} signaling following mitochondrial dysfunction that governs neuronal cell death by dissembling nuclear architecture. Exposing N27 DAergic cell line to the mitochondrial complex-1 inhibitor tebufenpyrad induced PKC{delta} phosphorylation at the T505 activation loop accompanied by caspase-3-dependent proteolytic activation of the kinase. Subcellular analysis using high-resolution 3D confocal microscopy revealed that proteolytically activated cleaved PKC{delta} translocates to the nuclear compartment, colocalizing with Lamin B1. Electron microscopy also enabled the visualization of nuclear membrane damage triggered by subjecting the DAergic neuronal cells by Tebufenpyrad (Tebu) toxicity. In silico analyses identified that the threonine site on Lamin B1 (T575) is likely phosphorylated by PKC{delta}, suggesting that Lamin B1 serves as a key downstream target of the kinase. Interestingly, N27 DAergic cells stably expressing the PKC{delta} proteolytic cleavage site-resistant mutant failed to induce nuclear damage, PKC{delta} activation, and Lamin B1 phosphorylation. Furthermore, CRISPR/Cas9-based stable knockdown of PKC{delta} greatly attenuated Tebu-induced Lamin B1 phosphorylation. Also, studies using Lamin B1T575G mutated at phosphorylation and PKC{delta}-{Delta}NLS-overexpressing N27 cells showed that PKC{delta} activation and translocation to the nuclear membrane are critically required for phosphorylating Lamin B1 at T575 to induce nuclear membrane damage during Tebu insult. Additionally, Tebu failed to induce Lamin B1 damage and Lamin B1 phosphorylation in organotypic midbrain slices cultured from PKC{delta}-/- mouse pups. More importantly, we observed higher PKC{delta} activation, Lamin B1 phosphorylation and Lamin B1 loss in nigral DAergic neurons from the postmortem brains of PD patients as compared to age-matched healthy control brains, thus providing translational relevance of our finding. Collectively, our data reveal that PKC{delta} functions as a Lamin B1 kinase to disassemble the nuclear membrane during the neuronal cell death process triggered by mitochondrial stress. This mechanistic insight may have important implications for the etiology of age-related neurodegenerative diseases resulting from mitochondrial dysfunction as well as for the development of novel treatment strategies.

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↗

bioRxiv2020

How do neuroglial cells respond to ultrasound induced cavitation?

Reactive astrocytes are known to play a vital role in the overall response of the brain during a traumatic brain injury (TBI). Modern studies have speculated the existence of cavitation in the skull during a TBI, which has alarming potential to cause detrimental damages. Previous studies have confirmed the upregulation of various harmful genes in neurodegenerative diseases. Studying the longitudinal presence of these harmful genes in response to cavitation allows for optimized understanding and treatment methods in cavitation exposure. We seek to characterize the longitudinal genetic expression levels that astrocytes exhibit after exposure to cavitation and further elucidate the startling presence of cranial cavitation. Astrocytic expression levels of various common genes that have been documented in TBI research are our target of interest, like, TNF, IL-1{beta}, and NOS1. Results summarize specific gene trends from 1-48 hours after cavitation. Our data concludes that maximum expression is not consistently exhibited immediately after cavitation exposure, and most genes have individualized genetic trends. IL-1{beta} shows a decreasing expression over 48 hours, and TNF shows upregulation until the 6 hour time point but then begins to decrease in expression. The upregulation of NOS1 has been documented in neurodegenerative diseases, like Alzheimers and Parkinsons disease. This study has shown a consistent upregulation in NOS1 expression from 0-48 hours. These results postulate a possible linkage between cavitation damage and neurodegenerative diseases. This analysis also provides novelty in optimizing treatments for astrocytic function post-TBI and legitimizing the concern of cranial cavitation existence. These results add motivation for future studies of cavitation elimination or minimization via advanced helmet and airbag engineering.

bioengineering↗

bioRxiv2020

Organic dust induced mitochondrial dysfunction could be targeted via cGAS-STING or mitochondrial NOX-2 inhibition

ABSTRACTOrganic dust (OD) exposure in animal production industries poses serious respiratory and other health risks. OD consists of microbial products and particulate matter and OD exposure induced respiratory inflammation is under intense investigation. However, the effect of OD exposure on brain largely remains unknown. Recently, we have shown that OD exposure of brain microglial cells induces an inflammatory phenotype with the release of mitochondrial DNA (mt-DNA). Therefore, we tested a hypothesis that OD-exposure induced secreted mt-DNA signaling drives the inflammation. OD samples were collected from commercial swine operations and a filter sterilized OD extract (ODE) was prepared. Mouse (C57BL/6) microglial cell line was treated with medium or ODE (5%) for 48 hours along with either PBS or mitoapocynin (MA, 10 μM, NOX-2 inhibitor). Microglia treated with control or anti-STING siRNA were exposed to medium or ODE. Next, mouse (C57BL/6) pups were euthanized under an approved protocol, organotypic brain slice cultures (BSCs) were prepared and exposed to medium or ODE with or without MA treatment daily for five days. Culture supernatant, cell pellets and mt-free cytosolic fractions were processed to quantify mt-superoxide, mt-DNA, cytochrome C, TFAM, mitochondrial stress markers and mt-DNA induced signaling via cGAS-STING and TLR9. Data were analyzed using one-way ANOVA and post-hoc tests. A p value of ≤ 0.05 was considered significant. ODE exposure increased the mt-superoxide formation andMA treatment decreased the ODE-induced mt-DNA release into cytosol. ODE exposure increased the cytochrome C and TFAM levels. ODE increased MFN1/2 and PINK1 but not DRP1 and MA treatment decreased the MFN2 expression. MA treatment decreased the ODE-exposure induced mt-DNA signaling via cGAS-STING and TLR9. Anti-STING siRNA decreased the ODE-induced increase in IRF3, IFN-β and Iba1 expression. In BSCs, MA-treatment decreased the ODE induced TNF-α, IL-6 and MFN1. Taken together, OD exposure induced mt-DNA signaling could be curtailed through mitochondrial NOX-2 inhibition or STING suppression to reduce neuroinflammation.Competing Interest StatementAGK has an equity interest in PK Biosciences Corporation located in Ames, IA. The terms of this arrangement have been reviewed and approved by Iowa State University per its conflict of interest policies. All other authors have declared no potential conflicts of interest.View Full Text

cell biology↗

bioRxiv2020

Organic Dust Exposure Induces Stress Response and Mitochondrial Dysfunction in Monocytic Cells

Exposure to airborne organic dust (OD), rich in microbial pathogen-associated molecular patterns, has been shown to induce inflammatory responses in the lung resulting in changes in airway structure and function. A common manifestation in lung inflammation is the occurrence of altered mitochondrial structure and bioenergetics, consequently regulating mitochondrial ROS (mROS) and creating a vicious cycle of mitochondrial dysfunction.The role of mitochondrial dysfunction in airway diseases such as COPD and asthma is well known. However, whether OD exposure induces mitochondrial dysfunction largely remains unknown. Therefore, in this study, we tested a hypothesis that OD exposure induces mitochondrial stress using a human monocytic cell line (THP-1). We examined the mechanisms of organic dust extract (ODE) exposure-induced mitochondrial structural and functional changes in THP-1 cells.In addition, the effect of co-exposure to ethyl pyruvate (EP), a known anti-inflammatory agent, or mitoapocynin (MA), a mitochondria targeting NOX2 inhibitor was examined. Transmission electron microscopy images showed significant changes in cellular and organelle morphology upon ODE exposure. ODE exposure with and without EP co-treatment increased the mtDNA leakage into the cytosol. Next, ODE exposure increased the PINK1 and Parkin expression, cytoplasmic cytochrome c levels and reduced mitochondrial mass and cell viability, indicating mitophagy. MA treatment was partially protective by decreasing Parkin expression, mtDNA and cytochrome c release and increasing cell viability.Competing Interest StatementAGK has an equity interest in PK Biosciences Corporation located in Ames, IA. The terms of this arrangement have been reviewed and approved by Iowa State University per its conflict of interest policies. All other authors have declared no potential conflicts of interest. AbbreviationsODOrganic DustODEOrgaic Dust ExtractEPEthyl PyruvateMAMitoapocyninLPSLipopolysaccharidePGNPeptidoglycanPAMPsPathogen Associated Molecular PatternsCOPDChronic Obstructive Pulmonary DiseaseAHRAirway hyperresponsivenessROSReactive Oxygen SpeciesRNSReactive Nitrogen SpeciesATPAdenosine TriphosphateOXPHOSOxidative PhosphorylationHMGB1High Mobility Group Box 1STATSignal Transducer and Activator of TranscriptionTPPTriphenylphosphoniumMPTP1-Methyl-4-Phenyl-1,2,3,6-TetrahydropyridineiNOSinducible Nitric Oxide SynthaseNOXNADPH OxidaseMTT3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromideTEMTransmission Electron MicroscopyDMSODimethyl SufoxidemtND1mitochondrial NADH dehydrogenase 1MFNMitofusinOPA1Optic Atrophy 1DRP1Dynamin-related protein 1EREndoplasmic ReticulumPINK1PTEN- induced kinase 1BNIP3Bcl-2 Homology 3 (BH3)-onlyMPTMitochondrial Permeability TransitionCOX4i2Cytochrome C Oxidase subunit 4 isoform 2ETCElectron Transport ChainSOD2Superoxide Dismutase 2mtDAMPsmitochondrial Damage Associated Molecular PattersmtTFAmitochondrial Transcription Factor AMGCMultinucleated Giant CellFBRForeign Body ReactionsOMMOuter Mitochondrial MembraneIMMInner Mitochondrial MembraneIMSIntermembrane SpaceILInterleukincGAScyclic GMP-AMP synthaseTLRToll-like receptorRAGEReceptor for advanced glycation end productsVDACVoltage-dependent anion channelView Full Text

cell biology↗

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↗