Impairment of chaperone-mediated autophagy affects neuronal homeostasis through altered expression of DJ-1 and CRMP-2 proteins

In this study, we have manipulated CMA function through alterations of LAMP2A abundance of utilizing primary rat cortical neurons, to identify potential changes to the neuronal proteome occurring prior to actual toxic effects. We have identified a list of proteins with significant,>2-fold change in abundance following our manipulations, of which PARK7/DJ-1 – an anti-oxidant implicated in hereditary forms of Parkinson's Disease (PD), and DPYSL2/CRMP-2 – a microtubule-binding phosphoprotein involved in schizophrenia pathogenesis – were both found to have measurable effects on neuronal homeostasis and phenotype. Taken together, this study describes alterations in the abundance of neuronal proteins involved in neuropsychiatric disorders upon CMA manipulation, and suggests that such alterations may in part be responsible for the neurodegeneration observed upon CMA impairment in vivo.Graphical abstractChaperone-mediated autophagy (CMA) is implicated in the pathogenesis of multiple disorders affecting the central nervous system, but less is known of its involvement in non-pathological neuronal homeostasis. This schematic illustrates the primary findings of our study, namely that from a primary deficiency in chaperone-mediated autophagy - as manipulated by LAMP2A downregulation - does arise two distinct phenotypic alterations: 1) decreased DJ-1 abundance causing hypersensitivity of primary neurons to oxidative stress, and 2) retarded dendritic development in vitro by reduced CR...
Source: Molecular and Cellular Neuroscience - Category: Neuroscience Source Type: research