Suppression of the motor deficit in a mucolipidosis type IV mouse model by bone marrow transplantation.
Mucolipidosis IV (MLIV) is a severe lysosomal storage disorder, which results from loss of the TRPML1 channel. MLIV causes multiple impairments in young children, including severe motor deficits. Currently, there is no effective treatment. Using a Drosophila MLIV model, we showed previously that introduction of trpml+in phagocytic glia rescued the locomotor deficit by removing early dying neurons, thereby preventing amplification of neuronal death from cytotoxicity. Because microglia, which are phagocytic cells in the mammalian brain, are bone marrow derived, and cross the blood-brain barrier, we used a mouse MLIV model to test the efficacy of bone marrow transplantation (BMT). We found that BMT suppressed the reduced myelination and the increased caspase-3 activity due to loss of TRPML1. Using a rotarod test, we demonstrated that early BMT greatly delayed the motor impairment in the mutant mice. These data offer the possibility that BMT might provide the first therapy for MLIV.
Neuroscience Research Institute.|Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106, USA.|Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Marquis T
MT
Walker
Neuroscience Research Institute craig.montell@lifesci.ucsb.edu.|Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106, USA.|Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Craig
C
Montell
D000818:Animals; D001812:Blood-Brain Barrier; D016026:Bone Marrow Transplantation / Q000379:methods; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D053148:Caspase 3; D002478:Cells, Cultured; D004195:Disease Models, Animal; D008247:Lysosomes; D051379:Mice; D017628:Microglia / Q000502:physiology; D009081:Mucolipidoses / Q000378:metabolism / Q000628:therapy*; D009474:Neurons / Q000502:physiology; D050051:Transient Receptor Potential Channels / Q000378:metabolism / Q000627:therapeutic use*
C512321:Mcoln1 protein, mouse; D050051:Transient Receptor Potential Channels; D053148:Caspase 3