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Created with Fabric.js 1.4.5 Drug target Parkinson's disease Introduction Introduction nACh receptor nACh receptor Unfolded Protein Response Unfolded Protein Response Proof of principle Proof of principle Nicotine inhibits ATF6 translocation to the nucleus and eIF2a phosphorylation in mouse cortical neurons. Cells were immunostained for endogenous ATF6 by (p)eIF2a Exposure to three nicotinic ligands increases the formation of ER exit sites By Miel, Floris and Ella Tobacco smoking is correlated with a delayed onset of Parkinsons disease. Nicotine freely permeates the cellular plasma membrane and accumulates within intracellular organelles. Nanomolar concentrations of nicotine are sufficient to alter the intracellular assembly and trafficking of nAChRs. The effects of nicotine on nAChR upregulation occur at nanomolar nicotine concentrations (100200 nM) that are equivalent to the steady state nicotine concentration observed in chronic smokers. Nicotine (and other full and partial agonists) have been shown to increase ER exit sites (increasing effectivity of the ER),inhibits translocation of ATF6, and nicotine (not all agonists) seem to increase the size of the ER which might lead to a bigger Ca2+ buffer. This leads to a decrease ER stress,and thus to a decrease in neuronal cell death. Tobacco smoking is correlated with a delayed onset of Parkinson’s disease. Nicotine freely permeates the cellular plasma membrane and accumulates within intracellular organelles. Nanomolar concentrations of nicotine are sufficient to alter the intracellular assembly and trafficking of nAChRs. The effects of nicotine on nAChR upregulation occur at nanomolar nicotine concentrations (∼100–200 nM) that are equivalent to the steady state nicotine concentration observed in chronic smokers. Nicotine (and other full and partial agonists) have been shown to increase ER exit sites (increasing effectivity of the ER),inhibits translocation of ATF-6, and nicotine (not all agonists) seem to increase the size of the ER which might lead to a bigger Ca2+ buffer. This leads to a decrease ER stress,and thus to a decrease in neuronal cell death. nAChR increases the efficiency by which dopaminergic neurons export cargo from the ER via ER exit sites, thus reducing the protein burden and increasing efficiency. In addition, an increased ER size due to chaperoning can enable more efficient Ca2+ buffering, thereby improving the overall health of dopaminergic neurons and preventing their death. The UPR stress response is a vicious cycle; ATF6 is translocated from the ER to the Golgi and is cleaved by site 1 and site 2 proteases to release an N-terminal peptide. These are then translocated to the nucleus where they target UPR genes that enhance ER function and increase ER-stress. nAChR upregulation inhibits nuclear translocation of ATF6. Proof of effectiveness Proof of effectiveness The UPR or ER stress response tries to counteract the accumulation of misfolded proteins in three ways:- enhance the translation of Endoplasmic Reticulum-Associated Degradation components, therefore decreasing misfolded proteinaccumulation by enhancing degradation.- stimulate protein-folding chaperone translation- decrease overall protein translation and giving ERAD more time to degrade misfolded proteins.Ultimately, if the UPR is unable to resove the protein accumulation, it triggers apoptosis. a-Syn trafficking can be enhanced by nACHhR by:- increasing the formation of ER export sites, to counter the lack of forward trafficking of α-syn- increasing the formation of COPI-containing vesicles, which can influence the number and efficiency by which early and late endosomes are formed- influencing lysosomes by increasing the number of nicotine-bound nAChRs that are resistant to degradation and therefore have a longer half life. The nACH receptor, influencing the UPR, is emerging as a promising target in PD Parkinson's disease (PD) is a neurodegenerative disease and is characterized by the loss of dopaminergic neurons of the substantia nigra and the accumulation of intracellular inclusions (Lewy bodies) containing α-synuclein. Additional neuronal fields and neurotransmitter systems are disrupted in later stages of PD. Disruption of the motor system is the major clinical symptom. 'Non-motor' features progress and come to dominate the later stages of PD. Aging is the major risk factor for developing PD. There is a reduced risk to develop PD in tobacco smokers. Disease modification, especially via dopami-nergic therapies, has been the most important goal in drug therapies. Sincethe focus of research in PD has centered on pathogenesis, we want to explore a neuroprotective pathway: UPR, the cellular response that protects against endoplasmic reticulum stress.
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