title: Development of cerebellar pathology in the canine model of mucopolysaccharidosis type IIIA (MPS IIIA).
abstract: The temporal relationship between the onset of clinical signs in the mucopolysaccharidosis type IIIA (MPS IIIA) Huntaway dog model and cerebellar pathology has not been described. Here we sought to characterize the accumulation of primary (heparan sulfate) and secondary (G(M3)) substrates and onset of other changes in cerebellar tissues, and investigate the relationship to the onset of motor dysfunction in these animals. We observed that Purkinje cells were present in dogs aged up to and including 30.9 months, however by 40.9 months of age only ~12% remained, coincident with the onset of clinical signs. Primary and secondary substrate accumulation and inflammation were detected as early as 2.2 months and axonal spheroids were observed from 4.3 months in the deep cerebellar nuclei and later (11.6 months) in cerebellar white matter tracts. Degenerating neurons and apoptotic cells were not observed at any time. Our findings suggest that cell autonomous mechanisms may contribute to Purkinje cell death in the MPS IIIA dog.
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, South Australia 5001, Australia. Electronic address: Sofia.Hassiotis@sahmri.com.
authors.forename: Sofia
authors.initials: S
authors.lastname: Hassiotis
authors.affiliation: Institute of Veterinary, Animal and Biomedical Sciences, Massey University, Palmerston North 4442, New Zealand. Electronic address: R.D.Jolly@massey.ac.nz.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Jolly
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, South Australia 5001, Australia. Electronic address: Kim.Hemsley@sahmri.com.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Hemsley
mesh_terms: D000818:Animals; D058070:Asymptomatic Diseases; D016923:Cell Death; D002529:Cerebellar Nuclei / Q000473:pathology; D002531:Cerebellum / Q000737:chemistry / Q000473:pathology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D004285:Dogs; D006497:Heparan Sulfate / Q000032:analysis; D006801:Humans; D007249:Inflammation; D009043:Motor Activity; D009084:Mucopolysaccharidosis III / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D011689:Purkinje Cells / Q000473:pathology; D066127:White Matter / Q000473:pathology
chemical_list: D006497:Heparan Sulfate
keywords: Cerebellum; Dog; Lysosomal storage disorder; Mucopolysaccharidosis; Purkinje cell; Sanfilippo syndrome