Alban Gaultier, Ph.D.
· Multiple sclerosis
· Neurodegenerative diseases
Multiple sclerosis (MS) is a debilitating autoimmune disease in which myelin of the central nervous system is destroyed and survival of myelin-producing oligodendrocytes is compromised. The pathogenesis of MS is incompletely understood. Oligodendrocyte apoptosis may represent an early event in the development of MS, preceding the onset of autoimmunity. Removal of apoptotic celland cellular debris is critical for tissue homeostasis. Degenerated myelin debris is usually removed by phagocytosis but accumulates in demyelinating disorders including MS.
We are interested in the events that are leading to the induction of MS. Particularly, we are studying a protein called Low Density Lipoprotein Receptor-related Protein-1 (LRP1), also called CD91. LRP1 is a scavenger receptor with a key role in apoptotic cell engulfment. Besides mediating endocytosis of over forty ligands LRP1 also controls the permeability of the blood-brain barrier and mediates antigen crosspresentation.
Our data show that LRP1 is an essential receptor for myelin clearance in vitro, andfunctions as an inhibitor of inflammation. Furthermore, in an animal model of MS: Experimental Autoimmune Encephalomyelitis (EAE), genetic ablation of LRP1 in the myeloid lineage leads to a significant increase in the clinical scores and the incidence of inflammatory lesions in the spinal cord.
Our Hypothesis is that LRP1, by
directly mediating the removal of degenerated myelin and inhibiting
inflammation, participates in the regulation of MS initiation and/or
Gaultier A, Simon G, Niessen S, Dix M, Takimoto S, Cravatt BF, 3rd, et al. LDL receptor-related protein 1 regulates the abundance of diverse cell-signaling proteins in the plasma membrane proteome. Journal of proteome research. 2010;9(12):6689-95.
Gaultier A, Wu X, Le Moan N, Takimoto S, Mukandala G, Akassoglou K, et al. Low-density lipoprotein receptor-related protein 1 is an essential receptor for myelin phagocytosis. Journal of cell science. 2009;122(Pt 8):1155-62.
Gaultier A, Arandjelovic S, Niessen S, Overton CD, Linton MF, Fazio S, et al. Regulation of tumor necrosis factor receptor-1 and the IKK-NF-kappaB pathway by LDL receptor-related protein explains the antiinflammatory activity of this receptor. Blood. 2008;111(11):5316-25.
Gaultier A, Arandjelovic S, Li X, Janes J, Dragojlovic N, Zhou GP, et al. A shed form of LDL receptor-related protein-1 regulates peripheral nerve injury and neuropathic pain in rodents. The Journal of clinical investigation. 2008;118(1):161-72.