Mn is an essential element that becomes toxic at elevated cellular levels leading to the onset of an incurable neurotoxic syndrome. To date, research on Mn homeostasis and toxicosis in mammals has focused on the mechanisms of Mn influx but the identified influx transporters are neither specific for Mn nor regulated by cellular Mn levels. In contrast, the role of efflux of cytosolic Mn is understudied although efflux plays a significant role in maintaining homeostasis of other metals. The investigators have now identified an important role for efflux of Mn via uptake into the Golgi apparatus followed by secretion in maintaining cellular Mn levels and protecting against excess Mn accumulation during elevated exposure. Based on this, their goal is to elucidate the regulatory mechanisms governing Mn efflux by the Golgi to so as to better understand the role of this fundamental process in Mn homeostasis and in the development of Mn-induced neurotoxicity. The investigators'results indicate that uptake of Mn into the Golgi requires SPCA1, a Golgi-localized Ca/Mn pump and that SPCA1 rapidly traffics between the Golgi and endosomes. As subcellular trafficking of ion pumps regulate their activity, their first aim is to elucidate the role of SPCA1 trafficking in regulating Mn efflux. The investigators also discovered that increased intra-Golgi Mn induces rapid degradation of the Golgi protein GPP130 and that GPP130 levels impact Mn efflux and toxicity. Therefore, the second aim is to elucidate the mechanism by which GPP130 regulates Mn efflux and toxicity. Finally, as additional factors regulating Mn efflux remain to be identified, the third aim is to perform a genome wide RNAi screen for proteins that alter control of Mn by the Golgi. In the screen, a modified version of GPP130 will serve as a novel sensor of Golgi lumenal Mn. The proposed studies will provide mechanistic understanding of a crucial but unexplored aspect of Mn homeostasis that is directly relevant to the pathobiology of Mn-induced neurotoxicity. Public Health Relevance: Manganese is an environmental and occupational toxin that leads to the onset of a Parkinson-like neurologic disease with no cure. The proposed work will determine the mechanism by which Mn is removed from human cells. This will lay the foundation for making drugs that increase removal of cellular Mn for the treatment of Mn toxicity in the future. It will also enable us to determine if genetic or acquired defects in Mn removal exist in the population that increases the risk of developing Mn-induced neurotoxicity.
Manganese is an environmental and occupational toxin that leads to the onset of a Parkinson-like neurologic disease with no cure. The proposed work will determine the mechanism by which Mn is removed from human cells. This will lay the foundation for making drugs that increase removal of cellular Mn for the treatment of Mn toxicity in the future. It will also enable us to determine if genetic or acquired defects in Mn removal exist in the population that increase the risk of developing Mn-induced neurotoxicity.
| Mukhopadhyay, Somshuvra; Linstedt, Adam D (2013) Retrograde trafficking of AB? toxins: mechanisms to therapeutics. J Mol Med (Berl) 91:1131-41 |
| Mukhopadhyay, Somshuvra; Redler, Brendan; Linstedt, Adam D (2013) Shiga toxin-binding site for host cell receptor GPP130 reveals unexpected divergence in toxin-trafficking mechanisms. Mol Biol Cell 24:2311-8 |
