An autophagy-targeting peptide to treat chronic inflammatory demyelinating polyneuropathies

Abstract

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nerves evolving with diffuse sensory and motor symptoms. Although it is claimed that in neurodegenerative pathologies, a common feature is the failure of proteolytic systems to adequately eliminate aggregated or misfolded proteins, it has not been addressed whether autophagy, a central "clearance" system delivering damaged intracellular components to lysosomes, is affected in CIDP. The focus of the present investigation was therefore to determine if some defects exist in autophagy processes in this setting and if they can be corrected or minimized using an appropriate treatment targeting this survival pathway. Experiments were performed using a rat model mimicking human CIDP, also known as chronic experimental autoimmune neuritis (c-EAN), the disease establishment and development of which was followed at both the clinical and biological levels (indices of disease severity, histopathological alteration, cytokines and antibodies rates). Based on immunofluorescence and western immunoblotting experiments on sciatic nerves and spleen cells from c-EAN rats, we demonstrate that both, macroautophagy and chaperone-mediated autophagy (CMA), are significantly altered in non-neuronal cells of the peripheral nervous system. We show further that a 21-mer synthetic phosphopeptide called P140, known to target CMA and successfully used in pathological settings where CMA markers are overexpressed, considerably ameliorates the clinical and biological course of the disease in c-EAN rats. P140 displayed prophylactic and therapeutic effects, both in terms of disease intensity and chronicity, and preserved sciatic nerves from disease-related damages. Our findings uncover new disrupted molecular pathways in a c-EAN model and provide a proof-of-concept that targeting CMA might represent a promising therapeutic strategy for treating inflammatory neuropathies for which no disease-specific treatment is currently available.

Keywords: Autophagy; Inflammatory neuropathies; P140 peptide; Specifically-targeted therapies.