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

Abstract

The first two authors contributed equally to this work u-Synucleln (a-Syn) accounts, as a major component ofLewy 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 a-Syn oligomerization/aggregation and pathologies raises the key question of which molecular form of a-Syn (i.e. monomeric u-Syn, protofibrils or mature fibrils) represents the damage-inducing culprit in the scenario of synucieinopathies. We show that human a-Syn protofibrils (PFs) are potent activators of parallel proinflammatory signalling pathways (p38 and ERIO!2 MAP kinases and NF-KB) in microglial cells in vitro. Furthermore, stereotactic injection of a-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 a-synucieinopathies involves microglial activation through a-Syn released or extruded from cells with pathogenic a-Syn metabolism. Compounds that inhibit the MAPKlNF-KB pathways might be a promising pharmacological strategy for the treatment of the inflammatory component of synucieinopathies inciuding PD.Emerging evidence suggests that multiple factors, both genetic and acquired, contribute to the neurodegeneration of the dopaminergic cells of the substantia nigra observed in Parkinson's disease (PD) (1). A major breakthrough in the understanding ofthe etiopathogenesis ofPD has been a consequence of the finding of autosomal inherited monogenic PD due to defects in different loci, some of them

Targeting α-synuclein oligomers by protein-fragment complementation for drug discovery in synucleinopathies

“…The kinases and pathways involved in pathogenic αsyn phosphorylation have yet to be elucidated however studies have linked CK2, calcineurin, and p38 MAPK to cellular stress, PD, and αsyn 51-56 . Follow up screens of additional kinase inhibitors eliminated calcineurin, src family kinase, FGF-1R TK, and CK2 families of inhibitors as having activity in our assay, but suggested p38 MAPK inhibitors as putative targets for αsyn oligomerization.…”

The Multi-target Effects of CNI-1493: Convergence of Antiamylodogenic and Antiinflammatory Properties in Animal Models of Alzheimer’s Disease

“…The multitarget properties of CNI-1493 were further corroborated through differential effects of CNI-1493 and C1213 on the CRND8 mouse model. While CNI-1493 massively reduced Aβ plaque number and volume (14), the administration of C1213 merely reduced plaque volume at a statistically significant level. This difference suggests that microglial modulation through CNI-1493 is required for reduction of the plaque number.…”

“…Neuronal cell death induced by stereotactic injection of α-synuclein protofibrils in the rat substantia nigra could be markedly attenuated by intraperitoneal injection of CNI-1493 (14). Our group has previously shown that the MAPK inhibitor CNI-1493 can ameliorate the pathophysiology in TgCRND8 mice, a murine AD model that overexpresses human amyloid precursor protein (APP).…”

Neuromediators in inflammation—a macrophage/nerve connection

“…Here, progressive degeneration of dopaminergic neurons in the substantia nigra and a subsequent reduction of DA levels in the striatum are caused by various mechanisms including inflammation (Brundin et al, 2008). Microglia substantially contribute to PD likely due to the accumulation of a-synuclein, which promotes proinflammatory signalling in these cells (Wilms et al, 2009). Loss of DA might thus induce a vicious cycle, progressively enhancing death of dopaminergic neurons.…”