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

by Selleckchem | Nov 24 2023

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.

Comments:

Thank you for sharing this detailed and informative research summary on Parkinson's disease (PD) and the potential role of PTEN in its pathogenesis. Your findings shed light on the complex molecular mechanisms underlying PD and offer valuable insights into potential therapeutic strategies. PTEN, known for its involvement in various cellular processes, appears to play a crucial role in sensing oxidative stress and neurotoxicity, subsequently influencing Fyn kinase activation and contributing to dopaminergic cell death.

The identification of PTEN as a key regulator in PD opens new avenues for the development of targeted therapies. By understanding its role in modulating Fyn kinase activation and its impact on mitochondrial dysfunction and neuroinflammation, researchers and clinicians can explore novel treatment approaches that focus on these specific pathways.

The positive regulation of interleukin-1β (IL-1β) and the transcription of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) by PTEN also highlight the broader impact of this molecule on the inflammatory response, providing additional targets for intervention.

Your research underscores the importance of continued investigation into the molecular basis of PD and the potential therapeutic benefits of targeting PTEN. Further studies and clinical trials will be essential to validate these findings and translate them into effective treatments for individuals affected by this debilitating neurodegenerative disorder.