Peripheral nervous system neuropathology and progressive sensory impairments in a mouse model of Mucopolysaccharidosis IIIB.
The lysosomal storage pathology in Mucopolysaccharidosis (MPS) IIIB manifests in cells of virtually all organs. However, it is the profound role of the neurological pathology that leads to morbidity and mortality in this disease, and has been the major challenge to developing therapies. To date, MPS IIIB neuropathologic and therapeutic studies have focused predominantly on changes in the central nervous system (CNS), especially in the brain, and little is known about the disease pathology in the peripheral nervous system (PNS). This study demonstrates characteristic lysosomal storage pathology in dorsal root ganglia affecting neurons, satellite cells (glia) and Schwann cells. Lysosomal storage lesions were also observed in the myoenteric plexus and submucosal plexus, involving enteric neurons with enteric glial activation. Further, MPS IIIB mice developed progressive impairments in sensory functions, with significantly reduced response to pain stimulation that became detectable at 4-5 months of age as the disease progressed. These data demonstrate that MPS IIIB neuropathology manifests not only in the entire CNS but also the PNS, likely affecting both afferent and efferent neural signal transduction. This study also suggests that therapeutic development for MPS IIIB may benefit from targeting the entire nervous system.
Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA. haiyan.fu@nationwidechildrens.org
Haiyan
H
Fu
Julianne D
JD
Bartz
Robert L
RL
Stephens
Douglas M
DM
McCarty
D000818:Animals; D002490:Central Nervous System / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D017615:Enteric Nervous System / Q000502:physiology; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism; D006579:Heterozygote; D008247:Lysosomes / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008856:Microscopy, Fluorescence / Q000379:methods; D008959:Models, Neurological; D009084:Mucopolysaccharidosis III / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010146:Pain; D017933:Peripheral Nervous System / Q000378:metabolism / Q000503:physiopathology*; D012583:Schwann Cells / Q000378:metabolism; D015398:Signal Transduction