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

Aishwarya Mary Johnson, Sara Jose, Abdul Rasheed Palakkott, Farheen Badrealam Khan, Nanthini Jayabalan, Jaleel Kizhakkayil, Shamma Abdulla Ali AlNaqbi, Mark Gh Scott, Mohammed Akli Ayoub, Richard Gordon, Hariharan Saminathan

Research output: Contribution to journalArticlepeer-review

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. Graphical Abstract: [Figure not available: see fulltext.].

Original languageEnglish
Pages (from-to)462-475
Number of pages14
JournalJournal of NeuroImmune Pharmacology
Volume18
Issue number3
DOIs
Publication statusPublished - Sept 2023

Keywords

  • Fyn kinase
  • Neurodegeneration
  • Neuroinflammation
  • PTEN
  • Parkinson’s disease
  • VO-OHpic

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

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