title: Peripheral nerve and neuromuscular junction pathology in Pompe disease.
abstract: Pompe disease is a systemic metabolic disorder characterized by lack of acid-alpha glucosidase (GAA) resulting in ubiquitous lysosomal glycogen accumulation. Respiratory and ambulatory dysfunction are prominent features in patients with Pompe yet the mechanism defining the development of muscle weakness is currently unclear. Transgenic animal models of Pompe disease mirroring the patient phenotype have been invaluable in mechanistic and therapeutic study. Here, we demonstrate significant pathological alterations at neuromuscular junctions (NMJs) of the diaphragm and tibialis anterior muscle as prominent features of disease pathology in Gaa knockout mice. Postsynaptic defects including increased motor endplate area and fragmentation were readily observed in Gaa(-/-) but not wild-type mice. Presynaptic neuropathic changes were also evident, as demonstrated by significant reduction in the levels of neurofilament proteins, and alterations in axonal fiber diameter and myelin thickness within the sciatic and phrenic nerves. Our data suggest the loss of NMJ integrity is a primary contributor to the decline in respiratory and ambulatory function in Pompe and arises from both pre- and postsynaptic pathology. These observations highlight the importance of systemic phenotype correction, specifically restoration of GAA to skeletal muscle and the nervous system for treatment of Pompe disease.
authors.affiliation: Department of Pediatrics Powell Gene Therapy Center falkd@ufl.edu bbyrne@ufl.edu.
authors.forename: Darin J
authors.initials: DJ
authors.lastname: Falk
authors.affiliation: Department of Pediatrics Powell Gene Therapy Center.
authors.forename: Adrian Gary
authors.initials: AG
authors.lastname: Todd
authors.affiliation: Department of Neuroscience and.
authors.forename: Sooyeon
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Pediatrics Powell Gene Therapy Center.
authors.forename: Meghan S
authors.initials: MS
authors.lastname: Soustek
authors.affiliation: Department of Pediatrics.
authors.forename: Mai K
authors.initials: MK
authors.lastname: ElMallah
authors.affiliation: Department of Physical Therapy, University of Florida, Gainesville, FL 32610, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Fuller
authors.affiliation: Department of Neuroscience and.
authors.forename: Lucia
authors.initials: L
authors.lastname: Notterpek
authors.affiliation: Department of Pediatrics Powell Gene Therapy Center falkd@ufl.edu bbyrne@ufl.edu.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
mesh_terms: D000818:Animals; D003964:Diaphragm / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006009:Glycogen Storage Disease Type II / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology*; D010791:Phrenic Nerve / Q000378:metabolism / Q000473:pathology*; D013977:Tibia / Q000378:metabolism / Q000473:pathology
chemical_list: C486253:Gpaa1 protein, mouse; D008562:Membrane Glycoproteins