Alpha-Synuclein Proteins Promote Pro-Inflammatory Cascades in Microglia: Stronger Effects of the A53T Mutant.
Parkinson's disease (PD) is histologically described by the deposition of α-synuclein, whose accumulation in Lewy bodies causes dopaminergic neuronal death. Although most of PD cases are sporadic, point mutations of the gene encoding the α-synuclein protein cause inherited forms of PD. There are currently six known point mutations that result in familial PD. Oxidative stress and neuroinflammation have also been described as early events associated with dopaminergic neuronal degeneration in PD. Though it is known that microglia are activated by wild-type α-synuclein, little is known about its mutated forms and the signaling cascades responsible for this microglial activation. The present study was designed to investigate consequences of wild-type and mutant α-synuclein (A53T, A30P and E46K) exposure on microglial reactivity. Interestingly, we described that α-synuclein-induced microglial reactivity appeared to be peptide-dependent. Indeed, the A53T protein activated more strongly microglia than the wild-type α-synuclein and other mutants. This A53T-induced microglial reactivity mechanism was found to depend on phosphorylation mechanisms mediated by MAPKs and on successive NFkB/AP-1/Nrf2 pathways activation. These results suggest that the microgliosis intensity during PD might depend on the type of α-synuclein protein implicated. Indeed, mutated forms are more potent microglial stimulators than wild-type α-synuclein. Based on these data, anti-inflammatory and antioxidant therapeutic strategies may be valid in order to reduce microgliosis but also to subsequently slow down PD progression, especially in familial cases.
Life Sciences Research Unit, Laboratory of Neurobiology, University of Luxembourg, Faculty of Science, Technology and Communication, 7, avenue des Hauts Fourneaux, L-4362, Esch-sur-Alzette, Luxembourg.
Claire
C
Hoenen
Life Sciences Research Unit, Laboratory of Neurobiology, University of Luxembourg, Faculty of Science, Technology and Communication, 7, avenue des Hauts Fourneaux, L-4362, Esch-sur-Alzette, Luxembourg.
Audrey
A
Gustin
Life Sciences Research Unit, Laboratory of Neurobiology, University of Luxembourg, Faculty of Science, Technology and Communication, 7, avenue des Hauts Fourneaux, L-4362, Esch-sur-Alzette, Luxembourg.
Cindy
C
Birck
Life Sciences Research Unit, Laboratory of Neurobiology, University of Luxembourg, Faculty of Science, Technology and Communication, 7, avenue des Hauts Fourneaux, L-4362, Esch-sur-Alzette, Luxembourg.
Mélanie
M
Kirchmeyer
Life Sciences Research Unit, Laboratory of Neurobiology, University of Luxembourg, Faculty of Science, Technology and Communication, 7, avenue des Hauts Fourneaux, L-4362, Esch-sur-Alzette, Luxembourg.
Nicolas
N
Beaume
Life Sciences Research Unit, Laboratory of Neurobiology, University of Luxembourg, Faculty of Science, Technology and Communication, 7, avenue des Hauts Fourneaux, L-4362, Esch-sur-Alzette, Luxembourg.
Paul
P
Felten
Life Sciences Research Unit, Laboratory of Neurobiology, University of Luxembourg, Faculty of Science, Technology and Communication, 7, avenue des Hauts Fourneaux, L-4362, Esch-sur-Alzette, Luxembourg.
Luc
L
Grandbarbe
Life Sciences Research Unit, Laboratory of Neurobiology, University of Luxembourg, Faculty of Science, Technology and Communication, 7, avenue des Hauts Fourneaux, L-4362, Esch-sur-Alzette, Luxembourg.
Paul
P
Heuschling
Life Sciences Research Unit, Laboratory of Neurobiology, University of Luxembourg, Faculty of Science, Technology and Communication, 7, avenue des Hauts Fourneaux, L-4362, Esch-sur-Alzette, Luxembourg.
Tony
T
Heurtaux
D019943:Amino Acid Substitution; D000818:Animals; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism*
D018836:Inflammation Mediators; D050505:Mutant Proteins; D017382:Reactive Oxygen Species; D051844:alpha-Synuclein