Translation modulators to preserve neurodegenerative decline and from metal toxicity (Part II)

Manganese (Mn) toxicity has long been linked to the neurodegenerative movement disorder of occupational manganism and also has long been associated with Parkinson’s disease (PD). We collaborated with Prof. Fudi Wang (Zhejiang University) to conduct a meta-analysis demonstrating that environmental excesses of Mn are statistically linked with impaired childhood neurodevelopment and cognition (Liu W, et al, Environ Health. 2020, 2;19(1):104). Here, we present support that Mn, and also Lead (Pb), exposures to brain neurons dysregulate iron transport to cause a neurodegenerative ferroptosis that might jeopardize cognitive function. We reviewed how high Mn and Pb exposures perturb iron homeostasis Rogers JT, Cahill CM.

The Alzheimer’s amyloid precursor protein (APP) cytoprotectively exports excess toxic Fe from neurons after binding to the central iron exporter ferroportin (FPN) (Venkataramani et al, 2018). As a part of normal cellular physiology, increases in intracellular iron concentrations induce the up-regulation of APP gene expression at the level of translation by relieving of repression by the Iron-regulatory Protein-1 (IRP1) acting at the site of an iron-responsive element RNA stem loop (IRE) in the 5’untranslated region (5’UTR) or APP mRNA. Resulting from these events, increased APP(s) levels have a protective role to promote excess iron efflux. The iron storage protein ferritin also is translationally up-regulated to confer cyto-protection via its ferroxidase activity (in the H- subunit). 
We discuss our model that Mn and Pb can both operate in model SH-SY5Y neural cell lines and in rodents to selectively interfere with the translation of ferritin and APP by a post-transcriptional mechanism to explain environmental metallo-neurotoxicities both ex vivo and in vivo. We review our findings that overexposures to Mn and Pb cause toxicity to neurons by targeting 5’UTR specific IREs amongst the network of iron-associated transcripts encoding proteins that promotes neuronal viability; this includes APP and ferritin whose Mn/Pb-induced absence increases iron load and may generate ferroptosis and cell death.

For a new therapy, the purine urate’s elevation emerged as a neuroprotective strategy to treat Mn induced neurologic disorders based on convergent bioinformatics studies of Mn induced gene cohorts in SH-SY5Y cells models.  This therapeutic strategy was supported also by epidemiological and clinical biomarker data as well as on its antioxidant and metal chelator properties. We present our findings that the use of urate, and our neuroprotective APP/ferritin 5’UTR activators, indeed mitigate Mn/Pb induced degeneration of cultured dopaminergic neurons.  Activators of IRE-target sequences are to be tested for their capacity to restore translation of the mRNAs for APP (neuroprotective iron export) and ferritin (neuroprotective iron storage) after their inhibition in the presence of Mn or Pb.  Among the activators, we describe clinical aspects of urate’s neuroprotective potential to ward off Mn and Pb dependent neuronal injury via IRE-mediated pathways.

Jack Rogers, PhD. is a leading authority on the maintenance of iron homeostasis related to investigating its modulatory action on RNA metabolism in disease processes in neurodegeneration, including manganese neurotoxicity and Parkinson’s disease (PD). He is the co-Director of the Neurochemistry Program in the Psychiatry/ NEUROSCIENCE Department at Massachusetts General Hospital. Jack works closely with his partner Dr. Catherine Cahill in their joint effort for establishing novel therapies to treat and retard iron imbalances and ferroptosis that can accelerate the neurodegeneration of PD and Alzheimer’s Disease. He is an Associate Professor at the Harvard Medical School, having a funded track-record in established scientific journals (Cell, J. Biol. Chem. and PNAS.). His peer review publications won him a Zenith award from the Alzheimer’s Association on translational control by iron and related disease progression. The team is contributing efforts for small molecule drug discovery for treatments of neurodegenerative and neurodevelopmental disease. They are advancing novel pharmacological therapies in order to offset the manganese induced neurotoxicity that can generate Parkinsonian ferroptosis and undermine neural survival.