Central nervous system pathology in preclinical MPS IIIB dogs reveals progressive changes in clinically relevant brain regions

Martin T. Egeland, Marta M. Tarczyluk-Wells, Melissa M. Asmar, Evan G. Adintori, Roger Lawrence, Elizabeth M. Snella, Jackie K. Jens, Brett E. Crawford, Jill C.M. Wait, Emma McCullagh, Jason Pinkstaff, Jonathan D. Cooper, N. Matthew Ellinwood

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B) is an autosomal recessive lysosomal storage disorder caused by the deficiency of alpha-N-acetylglucosaminidase activity, leading to increased levels of nondegraded heparan sulfate (HS). A mouse model has been useful to evaluate novel treatments for MPS IIIB, but has limitations. In this study, we evaluated the naturally occurring canine model of MPS IIIB for the onset and progression of biochemical and neuropathological changes during the preclinical stages (onset approximately 24–30 months of age) of canine MPS IIIB disease. Even by 1 month of age, MPS IIIB dogs had elevated HS levels in brain and cerebrospinal fluid. Analysis of histopathology of several disease-relevant regions of the forebrain demonstrated progressive lysosomal storage and microglial activation despite a lack of cerebrocortical atrophy in the oldest animals studied. More pronounced histopathology changes were detected in the cerebellum, where progressive lysosomal storage, astrocytosis and microglial activation were observed. Microglial activation was particularly prominent in cerebellar white matter and within the deep cerebellar nuclei, where neuron loss also occurred. The findings in this study will form the basis of future assessments of therapeutic efficacy in this large animal disease model.

Original languageEnglish
Article number20365
JournalScientific reports
Volume10
Issue number1
DOIs
StatePublished - Dec 2020

Fingerprint

Dive into the research topics of 'Central nervous system pathology in preclinical MPS IIIB dogs reveals progressive changes in clinically relevant brain regions'. Together they form a unique fingerprint.

Cite this