ER Stress Marker GRP78 Colocalizes with LRRK2 in Human Parkinson’s Disease. (P2.145)

Introduction: Glucose related Protein 78 (GRP78)[1], a key signaling molecule of endoplasmic reticulum (ER) stress[2], and leucine-rich repeat kinase 2 (LRRK2)[3], represent promising therapeutic targets of Parkinson’s Disease (PD)[4, 5]. GRP78 protects cells in early stages of ER stress[2] and LRRK2 is the leading genetic cause of PD[3]. We earlier showed that LRRK2 upregulates GRP78, through p38 pathway, in response to 6-hydroxydopamine exposure or human α-synuclein over-expression in dopaminergic neurons of C. elegans, human neuroblastoma cells and murine cortical neurons[6]. Here, we present neuropathological evidence for relationship of GRP78 and LRRK2 in human PD. Materials & Methods: We performed immuno-staining of adjacent serial sections of the substantia nigra of 9 PD (neuropathologically confirmed Lewy bodies) patients (aged 53-84) and 4 age-matched controls. Results: We found co-localization of GRP78 with activated p38 and LRRK2 in the cytoplasm of dopaminergic neurons. Such co-localized immunoreactivity was not observed in 4 age-matched controls. Co-localization of GRP78 with activated p38 and LRRK2 in the cytoplasm of dopaminergic neurons of PD patients. Conclusions: We propose that there is a potential relationship of ER stress, and its regulator GRP78, with LRRK2 in PD. This relationship may have important diagnostic and therapeutic implications in PD. Work In Progress: Researchers are actively exploring the role of ER stress and GRP78 as key players in the pathogenesis of PD[7], including LRRK2 associated genetic PD[8]. Our report provides supportive evidence for such a potential relationship in the context of human PD pathology. We are further investigating the role of GRP78, the key regulator of ER stress, in living PD patients and controls. Disclosure: Dr. Gupta has nothing to disclose. Dr. Feng has nothing to disclose.