#Degradation of #misfolded, #damaged or #unneeded #proteins have a #crucial #role in #maintenance and #regulation of #cellular #function. #Environmental #exposure #pesticides #ALS #MND #neurodegenerative #disorders #cancer #Parkinsons #AD Excerpt from Pesticides and human chronic diseases: evidences, mechanisms, and perspectives. By Mostafalou S1, Abdollahi There are two major cellular mechanisms for protein degradation; ubiquitin proteasome system (UPS) that mainly targets short-lived proteins by proteases, and autophagy that mostly clears long-lived and poorly soluble proteins through the lysosomal machinery (Gies et al., 2010). UPS is composed of ubiquitin for tagging and proteasomes for proteolysis of proteins, which are to be degraded. Deregulation of this system has been implicated in the pathogenesis of several chronic diseases, mostly neurodegeneration and cancers evidenced by decreased and increased proteasome activity, respectively (Paul, 2008). Environmental exposure to certain pesticides has been linked to proteasomal dysfunction in development of neurodegenerative diseases. The organochlorine pesticide dieldrin has been reported to decrease proteasome activity along with enhanced sensitivity to occurrence of apoptosis in dopaminergic neuronal cells (Sun et al., 2005). Proteasome inhibition has also been shown in neuroblastoma cells exposed to rotenone, ziram, diethyldithiocarbamate, endosulfan, benomyl, and dieldrin (Chou et al., 2008 and Wang et al., 2006). Paraquat has also been noted to impair UPS given by decreased proteasome activity and increased ubiquitinated proteins in DJ-1 deficient mice and dopaminergic neurons (Yang and Tiffany-Castiglioni, 2007 and Yang et al., 2007). Increased degradation of proteasome components has been presented as the mechanism of proteasome inhibition by rotenone, an inducer of Parkinson (Chou et al., 2010). The lysosomal degradation pathway of autophagy is known as a self-digestion process by which cells not only get rid of misfolded proteins, damaged organelles and infectious microorganisms but also provide nutrients during fasting. Defect of this process has found an emerging role in many human diseases such as cancer, neurodegeneration, diabetes, aging, and disorders of the liver, muscle, and heart (Gonzalez et al., 2011, Levine and Kroemer, 2008 and Shintani and Klionsky, 2004). There are a few reports on the involvement of defective autophagy in toxic effects of pesticides. A relationship between autophagy and paraquat-induced apoptosis in neuroblastoma cells was shown by Gonzalez-Polo and colleagues in 2007 (Gonzalez-Polo et al., 2007). This effect was confirmed in another study in which paraquat-induced autophagy was attributed to the occurrence of ER stress (Niso-Santano et al., 2011). Lindan, a broad-spectrum organochlorine pesticide, has been reported to promote its toxicity through disruption of an autophagic process in primary rat hepatocytes (Zucchini-Pascal et al., 2009) (Fig. 3). Toxicol Appl Pharmacol. 2013 Apr 15;268(2):157-77. doi: 10.1016/j.taap.2013.01.025. Epub 2013 Feb 9.
Posted on: Fri, 26 Dec 2014 22:21:06 +0000
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