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Pharmacological Inhibition of PTEN Rescues Dopaminergic Neurons by Attenuating Apoptotic and Neuroinflammatory Signaling Events

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Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta resulting in an irreversible and a debilitating motor dysfunction. Though both genetic and idiopathic factors are implicated in the disease etiology, idiopathic PD comprise the majority of clinical cases and is caused by exposure to environmental toxicants and oxidative stress. Fyn kinase activation has been identified as an early molecular signaling event that primes neuroinflammatory and neurodegenerative events associated with dopaminergic cell death. However, the upstream regulator of Fyn activation remains unidentified. We investigated whether the lipid and tyrosine phosphatase PTEN (Phosphatase and Tensin homolog deleted on chromosome 10) could be the upstream regulator of Fyn activation in PD models as PTEN has been previously reported to contribute to Parkinsonian pathology. Our findings, using bioluminescence resonance energy transfer (BRET) and immunoblotting, indicate for the first time that PTEN is a critical early stress sensor in response to oxidative stress and neurotoxicants in in vitro models of PD. Pharmacological attenuation of PTEN activity rescues dopaminergic neurons from neurotoxicant-induced cytotoxicity by modulating Fyn kinase activation. Our findings also identify PTEN’s novel roles in contributing to mitochondrial dysfunction which contribute to neurodegenerative processes. Interestingly, we found that PTEN positively regulates interleukin-1β (IL-1β) and the transcription of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Taken together, we have identified PTEN as a disease course altering pharmacological target that may be further validated for the development of novel therapeutic strategies targeting PD.

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Data Availability

The data that support the findings of this study are available from the corresponding author (Aishwarya Mary Johnson) upon request.

References

  • Albornoz EA, Woodruff TM, Gordon R (2018) Inflammasomes in CNS diseases. Inflammasomes: Clinical and Therapeutic Implications. Springer 41-60

  • Ayoub MA, Landomiel F, Gallay N, Jégot G, Poupon A, Crépieux P, Reiter E (2015a) Assessing gonadotropin receptor function by resonance energy transfer-based assays. Front Endocrinol 6:130

  • Ayoub MA, Zhang Y, Kelly RS, See HB, Johnstone EK, McCall EA, Williams JH, Kelly DJ, Pfleger KD (2015b) Functional interaction between angiotensin II receptor type 1 and chemokine (CC motif) receptor 2 with implications for chronic kidney disease. PLoS One 10(3):e0119803

  • Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA (2009) Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. The Journal of Immunology 183(2):787–791

    Article  CAS  PubMed  Google Scholar 

  • Benetatos J, Bennett RE, Evans HT, Ellis SA, Hyman BT, Bodea LG, Götz J (2020) PTEN activation contributes to neuronal and synaptic engulfment by microglia in tauopathy. Acta Neuropathologica 140(1):7–24. https://doi.org/10.1007/s00401-020-02151-9

  • Carracedo A, Pandolfi PP (2008) The PTEN–PI3K pathway: of feedbacks and cross-talks. Oncogene 27(41):5527–5541. https://doi.org/10.1038/onc.2008.247

  • Charest PG, Terrillon S, Bouvier M (2005) Monitoring agonist-promoted conformational changes of beta-arrestin in living cells by intramolecular BRET. EMBO Rep 6(4):334–340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Charli A, Jin H, Anantharam V, Kanthasamy A, Kanthasamy AG (2016) Alterations in mitochondrial dynamics induced by tebufenpyrad and pyridaben in a dopaminergic neuronal cell culture model. Neurotoxicology 53:302–313. https://www.sciencedirect.com/science/article/pii/S0161813X15000947

  • Cheng J, Liao Y, Dong Y, Hu H, Yang N, Kong X, Li S, Li X, Guo J, Qin L, Yu J (2020) Microglial autophagy defect causes parkinson disease-like symptoms by accelerating inflammasome activation in mice. Autophagy 16(12):2193–2205. https://doi.org/10.1080/15548627.2020.1719723

  • Cui W, Wang S, Wang Z, Wang Z, Sun C, Zhang Y (2017) Inhibition of PTEN Attenuates Endoplasmic Reticulum Stress and Apoptosis via Activation of PI3K/AKT Pathway in Alzheimer’s Disease. Neurochem Res 42(11):3052–3060

    Article  CAS  PubMed  Google Scholar 

  • Deora V, Lee JD, Albornoz EA, McAlary L, Jagaraj CJ, Robertson AA, Atkin JD, Cooper MA, Schroder K, Yerbury JJ (2020) The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins. Glia 68(2):407–421

    Article  PubMed  Google Scholar 

  • Diaz-Ruiz O, Zapata A, Shan L, Zhang Y, Tomac AC, Malik N, de la Cruz F, Bäckman CM (2009) Selective deletion of PTEN in dopamine neurons leads to trophic effects and adaptation of striatal medium spiny projecting neurons. PloS one 4(9):e7027-e7027. https://pubmed.ncbi.nlm.nih.gov/19750226

  • Domanskyi A, Geiβler C, Vinnikov IA, Alter H, Schober A, Vogt MA, Gass P, Parlato R, Schütz G (2011) Pten ablation in adult dopaminergic neurons is neuroprotective in Parkinson's disease models. FASEB J 25(9):2898–2910. https://www.ncbi.nlm.nih.gov/pubmed/21593433

  • Frere S, Slutsky I (2016) Targeting PTEN interactions for Alzheimer's disease. Nature Neurosci 19(3):416–418. https://doi.org/10.1038/nn.4248

  • Gary DS, Mattson MP (2002) PTEN regulates Akt kinase activity in hippocampal neurons and increases their sensitivity to glutamate and apoptosis. NeuroMol Med 2(3):261–269. https://doi.org/10.1385/NMM:2:3:261

  • Gericke A, Munson M, Ross AH (2006) Regulation of the PTEN phosphatase. Gene 374:1–9

    Article  CAS  PubMed  Google Scholar 

  • Ghosh A, Kanthasamy A, Joseph J, Anantharam V, Srivastava P, Dranka BP, Kalyanaraman B, Kanthasamy AG (2012) Anti-inflammatory and neuroprotective effects of an orally active apocynin derivative in pre-clinical models of Parkinson's disease. J Neuroinflammation 9:241. https://www.ncbi.nlm.nih.gov/pubmed/23092448

  • Gordon R, Albornoz EA, Christie DC, Langley MR, Kumar V, Mantovani S, Robertson AA, Butler MS, Rowe DB, O’Neill LA, Kanthasamy AG (2018) Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice. Sci Transl Med 10:eaah4066. https://doi.org/10.1126/scitranslmed.aah4066

  • Gordon R, Anantharam V, Kanthasamy AG, Kanthasamy A (2012) Proteolytic activation of proapoptotic kinase protein kinase Cδ by tumor necrosis factor α death receptor signaling in dopaminergic neurons during neuroinflammation. J Neuroinflammation 9:82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gordon R, Hogan CE, Neal ML, Anantharam V, Kanthasamy AG, Kanthasamy A (2011) A simple magnetic separation method for high-yield isolation of pure primary microglia. J Neurosci Methods 194(2):287–296. https://www.sciencedirect.com/science/article/pii/S0165027010006102

  • Gordon R, Singh N, Lawana V, Ghosh A, Harischandra DS, Jin H, Hogan C, Sarkar S, Rokad D, Panicker N, Anantharam V (2016) Protein kinase Cδ upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease. Neurobiol Dis 93:96–114. https://www.sciencedirect.com/science/article/pii/S0969996116300900

  • Guan Y, Yang F, Yao Q, Shi J, Wang G, Gu Z, Zhou F, Shen J (2015) Impacts of phosphatase and tensin homology deleted on chromosome ten (PTEN)-inhibiting chitosan scaffold on growth and differentiation of neural stem cells. Int J Clin Exp Med 8(8):14308–14315. https://www.ncbi.nlm.nih.gov/pubmed/26550415

  • Hariz M, Obeso JA (2017) What Would Dr. James Parkinson Think Today? I. The Role of Functional Neurosurgery for Parkinson's Disease. Mov Disord 32(1):2–4. https://www.ncbi.nlm.nih.gov/pubmed/28124429

  • Hasegawa Y, Inagaki T, Sawada M, Suzumura A (2000) Impaired cytokine production by peripheral blood mononuclear cells and monocytes/macrophages in Parkinson’s disease. Acta Neurologica Scandinavica 101(3):159–164

    Article  CAS  PubMed  Google Scholar 

  • He J, Long C, Huang Z, Zhou X, Kuang X, Liu L, Liu H, Tang Y, Fan Y, Ning J, Ma X (2017) PTEN Reduced UVB-Mediated Apoptosis in Retinal Pigment Epithelium Cells. Biomed Res Int 2017:3681707. https://www.ncbi.nlm.nih.gov/pubmed/28321407

  • Heales SJ, Menzes A, Davey GP (2011) Depletion of glutathione does not affect electron transport chain complex activity in brain mitochondria: Implications for Parkinson disease and postmortem studies. Free Radical Biology and Medicine 50(7):899–902

    Article  CAS  PubMed  Google Scholar 

  • Hou SQ, Ouyang M, Brandmaier A, Hao H, Shen WH (2017) PTEN in the maintenance of genome integrity: From DNA replication to chromosome segregation. Bioessays 39(10). https://www.ncbi.nlm.nih.gov/pubmed/28891157

  • Johnson AM, Ou Z-YA, Gordon R, Saminathan H (2022) Environmental neurotoxicants and inflammasome activation in Parkinson’s disease–a focus on the gut-brain axis. The international journal of biochemistry & cell biology 142:106113

    Article  CAS  Google Scholar 

  • Johnson TA, Singla DK (2018) PTEN inhibitor VO-OHpic attenuates inflammatory M1 macrophages and cardiac remodeling in doxorubicin-induced cardiomyopathy. Am J Physiol-Heart Circulatory Physiol 315(5):H1236–H1249. https://journals.physiology.org/doi/abs/10.1152/ajpheart.00121.2018

  • Jose S, Groves NJ, Roper KE, Gordon R (2022) Mechanisms of NLRP3 activation and pathology during neurodegeneration. Int J Biochem Cell Biol 151:106273. https://www.sciencedirect.com/science/article/pii/S1357272522001182

  • Kaul S, Anantharam V, Yang Y, Choi CJ, Kanthasamy A, Kanthasamy AG (2005) Tyrosine phosphorylation regulates the proteolytic activation of protein kinase Cδ in dopaminergic neuronal cells. Journal of Biological Chemistry 280(31):28721–28730

    Article  CAS  PubMed  Google Scholar 

  • Kaul S, Kanthasamy A, Kitazawa M, Anantharam V, Kanthasamy AG (2003) Caspase-3 dependent proteolytic activation of protein kinase Cδ mediates and regulates 1-methyl-4-phenylpyridinium (MPP+)-induced apoptotic cell death in dopaminergic cells: relevance to oxidative stress in dopaminergic degeneration. European Journal of Neuroscience 18(6):1387–1401

    Article  PubMed  Google Scholar 

  • Kim RH, Mak TW (2006) Tumours and tremors: how PTEN regulation underlies both. Br J Cancer 94(5):620–624. https://www.ncbi.nlm.nih.gov/pubmed/16495927

  • Korczyn AD, Hassin-Baer S (2015) Can the disease course in Parkinson's disease be slowed? BMC Med 13:295. https://www.ncbi.nlm.nih.gov/pubmed/26653056

  • Lee YR, Chen M, Pandolfi PP (2018) The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol 19(9):547–562. https://doi.org/10.1038/s41580-018-0015-0

  • Lima-Fernandes E, Misticone S, Boularan C, Paradis JS, Enslen H, Roux PP, Bouvier M, Baillie GS, Marullo S, Scott MG (2014) A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells. Nat Commun 5:4431

    Article  CAS  PubMed  Google Scholar 

  • Lin M, Chandramani-Shivalingappa P, Jin H, Ghosh A, Anantharam V, Ali S, Kanthasamy AG, Kanthasamy A (2012) Methamphetamine-induced neurotoxicity linked to ubiquitin-proteasome system dysfunction and autophagy-related changes that can be modulated by protein kinase C delta in dopaminergic neuronal cells. Neuroscience 210:308–332. https://www.ncbi.nlm.nih.gov/pubmed/22445524

  • Lohse MJ, Nuber S, Hoffmann C (2012) Fluorescence/bioluminescence resonance energy transfer techniques to study G-protein-coupled receptor activation and signaling. Pharmacol Rev 64(2):299–336

    Article  CAS  PubMed  Google Scholar 

  • Lungu C, Cedarbaum JM, Dawson TM, Dorsey ER, Faraco C, Federoff HJ, Fiske B, Fox R, Goldfine AM, Kieburtz K, Macklin EA (2021) Seeking progress in disease modification in Parkinson disease. Parkinsonism Relat Disord 90:134–141. https://www.ncbi.nlm.nih.gov/pubmed/34561166

  • Madeira MH, Boia R, Santos PF, Ambrósio AF, Santiago AR (2015) Contribution of Microglia-Mediated Neuroinflammation to Retinal Degenerative Diseases. Mediators Inflammation 673090. https://doi.org/10.1155/2015/673090

  • Maehama T, Dixon JE (1999) PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol 9(4):125–128. https://www.sciencedirect.com/science/article/pii/S0962892499015196

  • Martinon F, Tschopp J (2007) Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death & Differentiation 14(1):10–22

    Article  CAS  Google Scholar 

  • Mkaddem SB, Murua A, Flament H, Titeca-Beauport D, Bounaix C, Danelli L, Launay P, Benhamou M, Blank U, Daugas E, Charles N, Monteiro RC (2017) Lyn and Fyn function as molecular switches that control immunoreceptors to direct homeostasis or inflammation. Nat Commun 8(1):246

    Article  PubMed  PubMed Central  Google Scholar 

  • Ning K, Drepper C, Valori CF, Ahsan M, Wyles M, Higginbottom A, Herrmann T, Shaw P, Azzouz M, Sendtner M (2010) PTEN depletion rescues axonal growth defect and improves survival in SMN-deficient motor neurons. Hum Mol Genet 19(16):3159–3168. https://www.ncbi.nlm.nih.gov/pubmed/20525971

  • Nishimura M, Mizuta I, Mizuta E, Yamasaki S, Ohta M, Kaji R, Kuno S (2001) Tumor necrosis factor gene polymorphisms in patients with sporadic Parkinson's disease. Neurosci Lett 311(1):1–4. https://www.sciencedirect.com/science/article/pii/S0304394001021115

  • Ogino M, Ichimura M, Nakano N, Minami A, Kitagishi Y, Matsuda S (2016) Roles of PTEN with DNA Repair in Parkinson's Disease. Int J Mol Sci 17(6):954. https://pubmed.ncbi.nlm.nih.gov/27314344. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926487/

  • Olanow CW (2014) Parkinson disease: Gene therapy for Parkinson disease--a hope, or a dream? Nat Rev Neurol 10(4):186–187. https://www.ncbi.nlm.nih.gov/pubmed/24662536

  • Olanow CW, Obeso JA (2011) Levodopa toxicity and Parkinson disease: still a need for equipoise. Neurology 77(15):1416–1417. https://www.ncbi.nlm.nih.gov/pubmed/21917774

  • Pajares M, I. Rojo A, Manda G, Boscá L, Cuadrado A (2020) Inflammation in Parkinson's Disease: Mechanisms and Therapeutic Implications. Cells 9(7):1687. https://pubmed.ncbi.nlm.nih.gov/32674367. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408280/

  • Palacios-Moreno J, Foltz L, Guo A, Stokes MP, Kuehn ED, George L, Comb M, Grimes ML (2015) Neuroblastoma tyrosine kinase signaling networks involve FYN and LYN in endosomes and lipid rafts. PLoS Comput Biol 11(4):e1004130

    Article  PubMed  PubMed Central  Google Scholar 

  • Panicker N, Sarkar S, Harischandra DS, Neal M, Kam TI, Jin H, Saminathan H, Langley M, Charli A, Samidurai M, Rokad D (2019) Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia. J Exp Med 216(6):1411–1430. https://pubmed.ncbi.nlm.nih.gov/31036561. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547864/

  • Peng J, Stevenson FF, Doctrow SR, Andersen JK (2005) Superoxide dismutase/catalase mimetics are neuroprotective against selective paraquat-mediated dopaminergic neuron death in the substantial nigra: implications for Parkinson disease. J Biol Chem 280(32):29194–29198

    Article  CAS  PubMed  Google Scholar 

  • Przedborski S (2017) The two-century journey of Parkinson disease research. Nat Rev Neurosci 18(4):251–259. https://www.ncbi.nlm.nih.gov/pubmed/28303016

  • Reale M, Iarlori C, Thomas A, Gambi D, Perfetti B, Di Nicola M, Onofrj M (2009) Peripheral cytokines profile in Parkinson’s disease. Brain Behav Immun 23(1):55–63

    Article  CAS  PubMed  Google Scholar 

  • Rosivatz E, Matthews JG, McDonald NQ, Mulet X, Ho KK, Lossi N, Schmid AC, Mirabelli M, Pomeranz KM, Erneux C, Lam EW (2006) A Small-Molecule Inhibitor for Phosphatase and Tensin Homologue Deleted on Chromosome 10 (PTEN). ACS Chemical Biol 1(12):780–790. https://doi.org/10.1021/cb600352f

  • Roskoski Jr R (2005) Src kinase regulation by phosphorylation and dephosphorylation. Biochem Biophys Res Commun 331(1):1–14. https://www.ncbi.nlm.nih.gov/pubmed/15845350

  • Roskoski Jr R (2015) Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors." Pharmacol Res 94:9–25. https://www.ncbi.nlm.nih.gov/pubmed/25662515

  • Saminathan H, Asaithambi A, Anantharam V, Kanthasamy AG, Kanthasamy A (2011) Environmental neurotoxic pesticide dieldrin activates a non receptor tyrosine kinase to promote PKCdelta-mediated dopaminergic apoptosis in a dopaminergic neuronal cell model. Neurotoxicology 32(5):567–577. https://www.ncbi.nlm.nih.gov/pubmed/21801747

  • Saminathan H, Charli A, Luo J, Panicker N, Gordon R, Hostetter JM, Jin H, Anantharam V, Kanthasamy AG, Kanthasamy A (2020) Fyn kinase mediates pro-inflammatory response in a mouse model of endotoxemia: Relevance to translational research. European J Pharmacol 881:173259. https://www.sciencedirect.com/science/article/pii/S0014299920303514

  • Saminathan H, Ghosh A, Zhang D, Song C, Jin H, Anantharam V, Kanthasamy A, Kanthasamy AG (2021) Fyn Kinase-Mediated PKCδ Y311 Phosphorylation Induces Dopaminergic Degeneration in Cell Culture and Animal Models: Implications for the Identification of a New Pharmacological Target for Parkinson’s Disease. Front Pharmacol 12. https://www.frontiersin.org/article/10.3389/fphar.2021.631375

  • Sarn N, Jaini R, Thacker S, Lee H, Dutta R, Eng C (2021) Cytoplasmic-predominant Pten increases microglial activation and synaptic pruning in a murine model with autism-like phenotype. Mol Psychiatry 26(5):1458–1471. https://doi.org/10.1038/s41380-020-0681-0

  • Schapira AH, Patel S (2014) Targeting Mitochondria for Neuroprotection in Parkinson Disease. JAMA Neurol 71(5):537–538. https://doi.org/10.1001/jamaneurol.2014.64

  • Song C, Charli A, Luo J, Riaz Z, Jin H, Anantharam V, Kanthasamy A, Kanthasamy AG (2019) Mechanistic Interplay Between Autophagy and Apoptotic Signaling in Endosulfan-Induced Dopaminergic Neurotoxicity: Relevance to the Adverse Outcome Pathway in Pesticide Neurotoxicity. Toxicol Sci 169(2):333–352. https://www.ncbi.nlm.nih.gov/pubmed/30796443

  • Spina Nagy G, Kawamoto EM, Bridi JC (2021) The role of PTEN signaling in synaptic function: Implications in autism spectrum disorder. Neurosci Lett 759:136015. https://www.sciencedirect.com/science/article/pii/S0304394021003931

  • Stojkovska I, Wagner BM, Morrison BE (2015) Parkinson's disease and enhanced inflammatory response. Experimental Biol Med (Maywood, N.J.) 240(11):1387–1395 https://pubmed.ncbi.nlm.nih.gov/25769314. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935292/

  • Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140(6):805–820

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Lu G, Shen HM (2020a) The Long and the Short of PTEN in the Regulation of Mitophagy. Front Cell Developmental Biol 8. https://www.frontiersin.org/article/10.3389/fcell.2020.00299

  • Wang W, Wang X, Guo H, Cai Y, Zhang Y, Li H (2020b) PTEN inhibitor VO-OHpic suppresses TSC2(-) (/) (-) MEFs proliferation by excessively inhibiting autophagy via the PTEN/PRAS40 pathway. Exp Ther Med 19(6):3565–3570

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Li L, Wu Y, Zhang S, Ju Q, Yang Y, Jin Y, Shi H, Sun C (2022) CD44 deficiency represses neuroinflammation and rescues dopaminergic neurons in a mouse model of Parkinson’s disease. Pharmacol Res 177:106133. https://www.sciencedirect.com/science/article/pii/S1043661822000780

  • Wu ZS, Huang WL, Gong SJ (2019) Effect of adenovirus-mediated overexpression of PTEN on brain oxidative damage and neuroinflammation in a rat kindling model of epilepsy. Chinese Med J 132(21):2628–2635. https://journals.lww.com/cmj/Fulltext/2019/11050/Effect_of_adenovirus_mediated_overexpression_of.15.aspx

  • Yao X, Yu S, Jing X, Guo J, Sun K, Guo F, Ye Y (2020) PTEN inhibitor VO-OHpic attenuates GC-associated endothelial progenitor cell dysfunction and osteonecrosis of the femoral head via activating Nrf2 signaling and inhibiting mitochondrial apoptosis pathway. Stem Cell Research & Therapy 11(1):1–18

    Article  Google Scholar 

  • Zeng L, Jiang H, Ashraf GM, Liu J, Wang L, Zhao K, Liu M, Li Z, Liu R (2022) Implications of miR-148a-3p/p35/PTEN signaling in tau hyperphosphorylation and autoregulatory feedforward of Akt/CREB in Alzheimer’s disease. Molecular Therapy-Nucleic Acids 27:256–275

    Article  CAS  PubMed  Google Scholar 

  • Zhao M, Gao J, Cui C, Zhang Y, Jiang X, Cui J (2021) Inhibition of PTEN ameliorates secondary hippocampal injury and cognitive deficits after intracerebral hemorrhage: involvement of AKT/FoxO3a/ATG-Mediated autophagy. Oxidative Med Cellular Longevity 2021:5472605. https://doi.org/10.1155/2021/5472605

  • Zheng D, Liwinski T, Elinav E (2020) Inflammasome activation and regulation: Toward a better understanding of complex mechanisms. Cell discovery 6(1):1–22

    Article  Google Scholar 

  • Zheng J, Li H, Xu D, Zhu H (2017) Upregulation of tyrosine kinase FYN in human thyroid carcinoma: role in modulating tumor cell proliferation, invasion, and migration. Cancer Biother Radiopharm 32(9):320–326. https://www.ncbi.nlm.nih.gov/pubmed/29140740

  • Zhou J, Parada LF (2012) PTEN signaling in autism spectrum disorders. Curr Opin Neurobiol 22(5):873–879

    Article  CAS  PubMed  Google Scholar 

  • Zhu Y, Hoell P, Ahlemeyer B, Krieglstein J (2006) PTEN: A crucial mediator of mitochondria-dependent apoptosis. Apoptosis 11(2):197–207. https://doi.org/10.1007/s10495-006-3714-5

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Acknowledgements

HS is supported by United Arab University Grants - UAE-Research Start-Up 31F129. RG is supported by an Advance Queensland Mid-Career Fellowship and research grants from the Michael J Fox Foundation and the Shake It Up Australia Foundation. MGS provided the Rluc-PTEN-YFP plasmids for this study. The graphical abstract is developed using Biorender.com.

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  1. Aishwarya Mary Johnson and Sara Jose have contributed equally.

Authors and Affiliations

  1. Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, The United Arab Emirates University, P.O. Box 15551, Al Ain, UAE

    Aishwarya Mary Johnson, Shamma Abdulla Ali AlNaqbi & Hariharan Saminathan

  2. Centre for Microbiome Research, School of Biomedical Science, Translational Research Institute, Queensland University of Technology, Brisbane, 4102, Australia

    Aishwarya Mary Johnson, Nanthini Jayabalan & Richard Gordon

  3. Faculty of Medicine, The University of Queensland, Brisbane, Australia

    Sara Jose, Nanthini Jayabalan & Richard Gordon

  4. Department of Biology, College of Science, The United Arab Emirates University, P.O. Box 15551, Al Ain, UAE

    Abdul Rasheed Palakkott, Farheen Badrealam Khan & Mohammed Akli Ayoub

  5. Department of Nutrition and Health, College of Medical and Health Sciences, The United Arab Emirates University, P.O. Box 15551, Al Ain, UAE

    Jaleel Kizhakkayil

  6. UMR8104, Institut CochinCNRSUniversité de Paris, Inserm U1016, Paris, France

    Mark GH Scott

  7. Biology Department, College of Arts and Sciences, Khalifa University, P O Box 127788, Abu Dhabi, UAE

    Mohammed Akli Ayoub

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Contributions

AMJ and SJ are co-first authors in the study, and contributed equally to experiments. HS, RG and MAA conceptualized the hypothesis and supervised the project. ARP, FBK, NJ, SAAA and JK performed experiments. AMJ and SJ performed majority of the experiments and data analysis under the supervision of HS, RG, MAA, MGS. HS, AMJ, SJ, RG, MAA, contributed to the drafting of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Aishwarya Mary Johnson.

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Johnson, A.M., Jose, S., Palakkott, A.R. et al. Pharmacological Inhibition of PTEN Rescues Dopaminergic Neurons by Attenuating Apoptotic and Neuroinflammatory Signaling Events. J Neuroimmune Pharmacol 18, 462–475 (2023). https://doi.org/10.1007/s11481-023-10077-8

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