Suppression of Map Kinases Inhibits Microglial Activation and Attenuates Neuronal Cell Death Induced by α-Synuclein Protofibrils

Abstract

α-Synuclein (α-Syn) accounts, as a major component of Lewy bodies (LB), for the filamentous deposits in many cases of neurodegenerative diseases. Yet, little is known about the molecular mechanisms of neuronal loss in these diseases. The correlation between α-Syn oligomerization/aggregation and pathologies raises the key question of which molecular form of α-Syn (i.e. monomeric α-Syn, protofibrils or mature fibrils) represents the damage-inducing culprit in the scenario of synucleinopathies. We show that human α-Syn protofibrils (PFs) are potent activators of parallel proinflammatory signalling pathways (p38 and ERK1/2 MAP kinases and NF-κB) in microglial cells in vitro. Furthermore, stereotactic injection of α-Syn PFs into the substantia nigra of adult rats leads to a profound activation of microglia and adjacent neuronal cell loss, which can be attenuated by the MAP kinase inhibitor semapimod. We propose that the neurodegenerative process of α-synucleinopathies involves microglial activation through α-Syn released or extruded from cells with pathogenic α-Syn metabolism. Compounds that inhibit the MAPK/NF-κB pathways might be a promising pharmacological strategy for the treatment of the inflammatory component of synucleinopathies including PD.