Pharmacological inhibition of PTEN rescues dopaminergic neurons by attenuating apoptotic and neuroinflammatory signalling events

Abstract Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by a selective degeneration of dopaminergic neurons in the ventral mid-brain of humans called substantia nigra. This results in an irreversible and 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 due to environmental toxicants and oxidative stress. Activation of Fyn kinase has been implicated to be an early signalling event that primes both neuroinflammatory and neurodegenerative events associated with dopaminergic cell death. Fyn kinase is activated by dephosphorylation at the negatively regulating tyrosine site by tyrosine phosphatases. However, the tyrosine phosphatase that dephosphorylates and activates Fyn kinase is unidentified. One of the tyrosine phosphatases - PTEN (Phosphatase and Tensin homolog deleted on chromosome 10) a lipid and protein tyrosine phosphatase pathological roles in causing Parkinson’s disease has been previously studied in experimental models. We sought to study if PTEN would be the upstream regulator of Fyn activation in PD models. Our findings demonstrate for the first time that PTEN is a very early stress-sensor in response to oxidative stress and neurodegenerative toxicants in in vitro models of PD. Pharmacological inhibition of PTEN attenuates Fyn kinase and rescues dopaminergic neurons from neurotoxicants induced cytotoxicity. Our findings also identify PTEN’s additional and novel roles in contributing to mitochondrial dysfunction and neuroinflammatory pathways, both of which contribute to neurodegenerative processes. 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.