title: MFGE8 does not orchestrate clearance of apoptotic neurons in a mouse model of Parkinson's disease.
abstract: Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by a loss of dopaminergic neurons (DN) in the substantia nigra (SN). Several lines of evidence suggest that apoptotic cell death of DN is driven in part by non-cell autonomous mechanisms implicating microglial cells and inflammatory processes. Yet, how apoptotic DNs get removed by professional phagocytes and how this process modulates inflammatory processes are still unresolved issues. In this study, we investigated the role of MFGE8, a soluble factor involved in phagocytic recognition, in apoptotic DN clearance and neuroinflammation in PD. We report that glial expression of MFGE8 is enhanced in post-mortem PD brains compared to control individuals. Then, in vivo functional analysis of Mfge8 was assessed in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mouse model of PD using wild-type (WT) and Mfge8-deficient mice. Neuropathological analysis consisted in evaluating (i) the loss of nigral DN and striatal DN terminals, (ii) the extent of glial cell activation and (iii) the number of apoptotic profiles. In vivo microglial phagocytic activity was further assessed by measuring the engulfment of apoptotic DN preloaded with fluorescent latex beads. Here we show that Mfge8 deficiency neither impact the phagocytic clearance of apoptotic bodies nor change the overall neuropathological parameters (DN cell loss and glial cell activation). In summary, our data argue that MFGE8 is not likely involved in the phagocytic clearance of neuronal debris associated with nigrostriatal pathway injury.
authors.affiliation: CNRS, UMR 7225, Experimental Therapeutics of Neurodegeneration, F-75013 Paris, France.
authors.forename: Kiyoka
authors.initials: K
authors.lastname: Kinugawa
authors.forename: Yann
authors.initials: Y
authors.lastname: Monnet
authors.forename: Lixia
authors.initials: L
authors.lastname: Lu
authors.forename: Amaury J
authors.initials: AJ
authors.lastname: Bekaert
authors.forename: Clotilde
authors.initials: C
authors.lastname: Théry
authors.forename: Ziad
authors.initials: Z
authors.lastname: Mallat
authors.forename: Etienne C
authors.initials: EC
authors.lastname: Hirsch
authors.forename: Stéphane
authors.initials: S
authors.lastname: Hunot
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008894:Milk Proteins / Q000378:metabolism*; D009474:Neurons / Q000473:pathology*; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000954:Antigens, Surface; C098942:MFGE8 protein, human; C490919:Mfge8 protein, mouse; D008894:Milk Proteins