Investigating the possible role of LRP/LR in the pathogenesis of Parkinson’s Disease and cancer

Abstract

Currently, over 10 million people suffer from Parkinson’s disease (PD). α-synuclein and parkin are both implicated in PD, where mutations in α-synuclein result in its aggregation. However, the α-synuclein C-terminal domain (CTD) prevents this aggregation. Parkin, an E3 ubiquitin ligase, rescues cells from the effects of α-synuclein aggregation and in PD, mutations in parkin result in its loss-of-function. In addition, parkin has been suggested to be the link between PD and cancer. The 37kDa/67kDa Laminin Receptor Precursor/ high-affinity Laminin Receptor (LRP/LR)is a multifunctional receptor protein that plays a role in the pathogenesis of neurodegenerative disorders as well as cancer. This study aimed to determine the role of LRP/LR in PD and the effect that overexpressing LRP::FLAG has on colorectal cancer. To this end, human embryonic kidney (HEK293) cells and late-stage colorectal cancer cells (DLD-1) were stably transfected with pCIneo-LRP::FLAG and co-localization studies, western blot analysis, MTT cell viability and mitochondrial membrane potential assays were performed. In addition, co-localisation studies were done on neuroblastoma (SH-SY5Y)cells. The results show that LRP/LR and the human telomerase reverse transcriptase (hTERT) co-localise with the PD-related proteins -synuclein and parkin in SH-SY5Y cells. In addition, LRP/LR and -synuclein are shown to co-localise in HEK293 non-transfected and LRP::FLAG transfected cells. Furthermore, LRP::FLAG overexpression was shown to increase -synuclein CTD levels, cell viability and mitochondrial membrane potential in HEK293 cells. Interestingly, LRP::FLAG overexpression in DLD-1 cells decreased cell viability and mitochondrial membrane potential. LRP/LR was also shown to co-localise with parkin in DLD-1 non-transfected and LRP::FLAG transfected cells. However, hTERT and parkin were only found to co-localise in LRP::FLAG transfected cells. Finally, LRP::FLAG was shown to increase parkin levels in DLD-1 cells. In conclusion, this study shows that LRP/LR may play a protective role in PD and that LRP::FLAG overexpression could inhibit the progression of colorectal cancer. Therefore, therapeutic approaches aiming at increasing LRP/LR protein levels may represent a novel alternative for PD and cancer treatment