Jack T Rogers
Harvard University, USA
Title: Manganese disrupts Amyloid Precursor Protein (APP) and Ferritin Translation to induce Neuronal Metalotoxicity relevant to Parkinson’s Disease and Manganism
Biography
Biography: Jack T Rogers
Abstract
Manganese (Mn2+) is an essential trace element although occupational over-exposure to manganese has been linked to a neurodegenerative disease, termed Manganism that is uniquely related, but distinct from Parkinson’s disease. We demonstrated that Mn2+ dose-dependently inhibited translation of both the iron storage protein ferritin and iron-export amyloid precursor protein (APP), each as central iron homeostatic proteins that promote neuroprotective cellular survival in SH-SY5Y neuronal cells, rat brain, and in Parkinson’s disease brain tissue. This action was manifested via iron-responsive element (IRE) sequences in the 5’untranslated region (5’UTR) of the APP transcript. Levels of iron-regulatory protein-2 (IRP-2) translational repressor were decreased in response to Mn2+ influx suggesting that only sufficient levels of IRP1 remained and were therefore critical in the pathway of Mn2+ inhibition of both ferritin and APP translation. Consistently, Mn2+ toxicity was only modestly evident in cells up to 24 hours of exposure, even when these cells progressively exhibited total shut down of the ferritin /APP expression at the level of message translation. In this regard, the consequences of the loss of the protective axis of APP and ferritin expression against iron catalyzed oxidative stress became clear after 24 hours when we observed a consistent and timed dramatic fall in cell viability after 48 hours and 72 hours metal exposure. We conclude the Mn2+ toxicity is partly attributable to translational inhibition pathways operating on APP and ferritin such that their absence embargoes neuroprotective iron export and storage to increase neurotoxic reactive oxygen species (ROS) in these cells, with subsequent and rapid neurotoxicity.