Title : Urate restores APP translational expression and losses of neural cell viability from Mn exposure
Abstract:
The metabolism of the metal manganese (Mn) is known to be tightly linked to perturbations of iron homeostasis in people while excess Mn can cause clinical occupational Manganism, a movement disorder distantly related to Parkinson's disease (PD). Our meta-analysis was consistent with knowledge that environmental Mn over-exposure is a global problem in neurocognitive development and can damage childhood IQ in affected areas (Liu et al, 2020. Environ Health. 2020 Oct 2;19(1):104). To investigate its mechanisms, we had shown Mn exposures to neural cell lines caused an embargo of iron export and storage as mediated by inhibition of IRE/IRP dependent translation of both H-ferritin (Fe storage) and that of the amyloid precursor protein (APP) (Venkataramani et al, 2018., J Neurochemistry;147(6):831-848). APP interacts with ferroportin (FPN) and appears to cytoprotectively accelerate iron efflux via the APP/ FPN axis. Here, we report that urate co-treatment offers a 15 -30 % efficacy to rescue SH-SY5Y cells from toxic exposures of Mn while our western blot data showed Urate increased intracellular levels of neuroprotective APP. Ferritin is a known multi subunit shell that prevents ferroptosis during MPTP induced Parkinsonism. By contrast to APP, we found urate did not restore Mn inhibition of ferritin expression in model SH-SY5Y cells. These data are consistent with a model whereby urate selectively induces APP translation correlated with its facilitation of the iron exporter FPN, an event that would increase viability when cells challenged by excess Mn. Urate's observable therapeutic action to prevent Mn induced ferroptosis in neurons by inducing APP translation certainly complements its known capacity to activate NRF2 mediated protection of cells from oxidative stress. These findings should encourage critical tests concerning how best to formulate urate to enhance its capacity to activate APP translation, and the APP/FPN interaction, in vivo as an event to prevent excess toxic iron overload and oxidative stresses in people exposed to neural Mn overload.
