Suppression of MAP kinases inhibits microglial activation and attenuates neuronal cell death induced by alpha-synuclein protofibrils.

Alpha-Synuclein (alpha-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 alpha-Syn oligomerization/aggregation and pathologies raises the key question of which molecular form of alpha-Syn (i.e. monomeric alpha-Syn, protofibrils or mature fibrils) represents the damage-inducing culprit in the scenario of synucleinopathies. We show that human alpha-Syn protofibrils (PFs) are potent activators of parallel proinflammatory signalling pathways (p38 and ERK1/2 MAP kinases and NF-kappaB) in microglial cells in vitro. Furthermore, stereotactic injection of alpha-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 alpha-synucleinopathies involves microglial activation through alpha-Syn released or extruded from cells with pathogenic alpha-Syn metabolism. Compounds that inhibit the MAPK/NF-kappaB pathways might be a promising pharmacological strategy for the treatment of the inflammatory component of synucleinopathies including PD.

Effector-independent representations of simple and complex imagined finger movements: a combined fMRI and TMS study.

Kinesthetic motor imagery and actual execution of movements share a common neural circuitry. Functional magnetic resonance imaging was used in 12 right-handed volunteers to study brain activity during motor imagery and execution of simple and complex unimanual finger movements of the dominant and the nondominant hand. In the simple task, a flexible object was rhythmically compressed between thumb, index and middle finger. The complex task was a sequential finger-to-thumb opposition movement. Premotor, posterior parietal and cerebellar regions were significantly more active during motor imagery of complex movements than during mental rehearsal of the simple task. In 10 of the subjects, we also used transcranial magnetic brain stimulation to examine corticospinal excitability during the same motor imagery tasks. Motor-evoked potentials increased significantly over values obtained in a reference condition (visual imagery) during imagery of the complex, but not of the simple movement. Imagery of finger movements of either hand activated left dorsal and ventral premotor areas and the supplementary motor cortex regardless of task complexity. The effector-independent activation of left premotor areas was particularly evident in the simple motor imagery task and suggests a left hemispherical dominance for kinesthetic movement representations in right-handed subjects.