Abstract
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.
Highlights
Mucopolysaccharidosis (MPS) IIIB is a lysosomal storage disease caused by the autosomal recessive defect of a-Nacetylglucosaminidase (NaGlu) gene [1]
Research on MPS IIIB neuropathology and therapeutic development have been predominantly focused on the central nervous system (CNS), especially the brain, and little is known regarding the pathological changes in other aspects of the nervous system
We demonstrate here that the neuropathology is manifested in the CNS, and in the dorsal root ganglion and enteric nervous system, supporting the notion that the disease may affect a majority of, if not all, components of the nervous system
Summary
Mucopolysaccharidosis (MPS) IIIB is a lysosomal storage disease caused by the autosomal recessive defect of a-Nacetylglucosaminidase (NaGlu) gene [1]. Mutations are highly heterogenic among patients with MPS IIIB [1,2,3]. The lack of NaGlu activity results in the accumulation of HS and HS-derived oligosaccharides in lysosomes of cells in virtually all organs, especially cells throughout the central nervous system (CNS), including neuronal and nonneuronal cell-types, not all CNS cells are affected [4]. Patients with MPS IIIB appear normal at birth, but develop a progressive and severe neurological disorder, though somatic manifestations of MPS IIIB are relatively mild compared to other types of MPS. High mortality and premature death are typical in MPS IIIB patients.
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