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Evaluation of Disease Lesions in the Developing Canine MPS IIIA Brain

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JIMD Reports, Volume 43

Part of the book series: JIMD Reports ((JIMD,volume 43))

Abstract

Mucopolysaccharidosis IIIA (MPS IIIA) is an inherited neurodegenerative disease of childhood that results in early death. Post-mortem studies have been carried out on human MPS IIIA brain, but little is known about early disease development. Here, we utilised the Huntaway dog model of MPS IIIA to evaluate disease lesion development from 2 to 24 weeks of age. A significant elevation in primarily stored heparan sulphate was observed in all brain regions assessed in MPS IIIA pups ≤9.5 weeks of age. There was a significant elevation in secondarily stored ganglioside (GM3 36:1) in ≤9.5-week-old MPS IIIA pup cerebellum, and other brain regions also exhibited accumulation of this lipid with time. The number of neural stem cells and neuronal precursor cells was essentially unchanged in MPS IIIA dog brain (c.f. unaffected) over the time course assessed, a finding corroborated by neuron cell counts. We observed early neuroinflammatory changes in young MPS IIIA pup brain, with significantly increased numbers of activated microglia recorded in all but one brain region in MPS IIIA pups ≤9.5 weeks of age (c.f. age-matched unaffected pups). In conclusion, infant-paediatric-stage MPS IIIA canine brain exhibits substantial and progressive primary and secondary substrate accumulation, coupled with early and robust microgliosis. Whilst early initiation of treatment is likely to be required to maintain optimal neurological function, the brain’s neurodevelopmental potential appears largely unaffected by the disease process; further investigations confirming this are warranted.

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Abbreviations

CA3:

Cornus ammonis region 3

CV:

Coefficient of variation

FGF-2:

Fibroblast growth factor 2

Ganglioside species:

GD1, GM1, GM2, GM3, GT1

GC:

Glucosylceramide

GlcSph:

Glucosylsphingosine

LC:

Lactosylceramide

LIMP-2:

Lysosomal integral membrane protein-2

MPS-IIIA:

Mucopolysaccharidosis type IIIA

NeuN:

Neuronal nuclear antigen

PC:

Phosphatidylcholine

PE:

Phosphatidylethanolamine

PG:

Phosphatidylglycerol

PI:

Phosphatidylinositol

PS:

Phosphatidylserine

SGSH:

Sulphamidase

SM:

Sphingomyelin

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Author information

Authors and Affiliations

  1. Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, SA, Australia

    Leanne K. Winner, Paul J. Trim, Stephen K. Duplock, Marten F. Snel & Kim M. Hemsley

  2. Institute of Veterinary, Animal and Biomedical Science, Massey University, Palmerston North, New Zealand

    Neil R. Marshall & Robert D. Jolly

Authors
  1. Leanne K. Winner
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  2. Neil R. Marshall
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  3. Robert D. Jolly
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  4. Paul J. Trim
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  5. Stephen K. Duplock
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  6. Marten F. Snel
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  7. Kim M. Hemsley
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Corresponding author

Correspondence to Kim M. Hemsley .

Editor information

Editors and Affiliations

  1. Tulane University Medical School, New Orleans, LA, USA

    Eva Morava

  2. Division of Metabolism & Children’s Research Centre, University Children’s Hospital Zürich, Zürich, Switzerland

    Matthias Baumgartner

  3. Division of Child and Adolescent Neurology, Mayo Clinic, Rochester, MN, USA

    Marc Patterson

  4. Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK

    Shamima Rahman

  5. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

    Johannes Zschocke

  6. Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany

    Verena Peters

Additional information

Communicated by: Carla E. Hollak, M.D.

Electronic Supplementary Material

Supplementary Fig. 1

Quantification of GM2 38:1 and GM3 38:1 in 2–24-week-old unaffected and MPS IIIA dog brain (a–f) and spinal cord (g, h). Each data point reflects a single dog. Six-week-old unaffected dog hippocampus was unavailable for study. The spinal cord was prepared in a separate batch from the brain (hippocampus, cortex and cerebellum). Two QC samples (MPS IIIA dog hippocampus) were run with each batch; both batches were analysed on the same day (DOCX 492 kb)

Supplementary Fig. 2

Quantification of the ganglioside GM3 precursors: (a) glucosylceramide (GC), and (b) lactosylceramide (LC); in addition to the most abundant species of phospholipids, (c) phosphatidylethanolamine (PE), and (d) phosphatidylinositol (PI), in the 2–24-week-old MPS IIIA and unaffected dog cerebellum. Each data point reflects a single dog (DOCX 83 kb)

Supplementary Fig. 3

Quantification of lipids in cerebellar samples taken from 2- to 24-week-old unaffected and MPS IIIA dogs. Each data point reflects a single dog. (a–d) Glucosylceramide (GC), (e–g) lactosylceramide (LC), (h) glucosylsphingosine (GlcSph) and (i–j) sphingomyelin (SM) (DOCX 559 kb)

Supplementary Fig. 4

Quantification of phospholipids in cerebellar homogenates taken from unaffected and MPS IIIA dogs aged 2–24 weeks. Each data point reflects a single dog. (a–c) Phosphatidylethanolamine (PE), (d–g) phosphatidylinositol (PI) and (h–k) phosphatidylserine (PS). The inter-assay CV for PE species was <14.1%, for PI species <12.1% and for PS species <13% (DOCX 618 kb)

Supplementary Fig. 5

Quantification of phospholipids in 2–24-week-old unaffected and MPS IIIA dog cerebellum. Each data point reflects a single dog. (a–d) Phosphatidylcholine (PC) and (e–i) phosphatidylglycerol (PG) (DOCX 316 kb)

Supplementary Fig. 6

Quantification of LIMP-2 immunoreactivity in various brain regions with time (a–e). Each data point reflects a single dog. Filled square 2-week-old pups, filled circle 4-week-old pups, filled triangle 6-week-old pups, filled diamond 9.5-week-old pups, filled inverted triangle 24-week-old pups. The photos in (f) show the location of the brain regions assessed: (a) gyrus suprasylvius anterior, (b) gyrus suprasylvius medialis, (c) polymorphic cell layer (hilus), (d) lobe 6 of the cerebellum and (e) caudate nucleus head. Photos in (g) and (h) show LIMP-2 staining in the gyrus suprasylvius anterior of 24-week-old unaffected and MPS IIIA dog brain (respectively). *p < 0.05, **p < 0.01 (DOCX 4573 kb)

Supplementary Fig. 7

Quantification of doublecortin immunoreactivity in various brain regions (a, b, d, e, g, h and j–l). Each data point reflects a single dog. The photos show doublecortin staining in the unaffected (c) and MPS IIIA (f) gyrus suprasylvius anterior at 2 weeks of age. The photos in (i) show the location of the brain regions assessed: (a) gyrus suprasylvius anterior, (b) gyrus suprasylvius medialis, (d) CA3, (e) dentate gyrus, (g) subventricular zone, (h) fasciculus subcallosus, (j–k) lobe 6 of the cerebellum and (l) caudate nucleus head (DOCX 1516 kb)

Supplementary Table 1

Ganglioside species assessed are listed in order of abundance, together with the inter-assay coefficient of variation for that species (DOCX 14 kb)

Supplementary Methods

(DOCX 22 kb)

Appendices

Synopsis

The infant-paediatric-stage mucopolysaccharidosis IIIA canine brain exhibits substantial and progressive primary and secondary substrate accumulation, with inflammatory changes that extend beyond substrate-accumulating brain regions; therapeutic intervention should occur at or soon after birth for the best outcome.

Contributions of Individual Authors

LKW carried out the experiments, analysed and interpreted the data and wrote the manuscript. NRM, RDJ, PJT, SKD and MFS carried out the experiments and interpreted the data. KMH designed the study, interpreted the data and wrote the manuscript.

Corresponding Author

Dr. Kim Hemsley, Lysosomal Diseases Research Unit, SAHMRI, PO Box 11060, Adelaide, SA, 5001, Australia. Kim.Hemsley@sahmri.com.

Competing Interest Statement

Leanne K. Winner declares that she has no conflict of interest.

Neil R. Marshall declares that he has no conflict of interest.

Robert D. Jolly declares that he has no conflict of interest.

Paul J. Trim declares that he has no conflict of interest.

Stephen K. Duplock declares that he has no conflict of interest.

Marten F. Snel declares that he has no conflict of interest.

Kim M. Hemsley declares that she has no conflict of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

Ethics Approval

All institutional and national guidelines for the care and use of laboratory animals were followed.

Documentation of Approval from the Institutional Committee for Care and Use of Laboratory Animals (or Comparable Committee)

The Massey University Animal Ethics Committee approved ethics application MUAEC 10/93 which states within: ‘Pups may be retained for breeding, used in other projects, re-homed or euthanased. Affected pups, and where indicated appropriate controls, will be grown within the existing colony. Any pups destined for clinical trials will be covered by a new animal ethics application. Pups/dogs not used in the longer term trials may be euthanased at varying ages to obtain tissues for biochemical and histological studies’.

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Winner, L.K. et al. (2018). Evaluation of Disease Lesions in the Developing Canine MPS IIIA Brain. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 43. JIMD Reports, vol 43. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2018_110

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  • DOI: https://doi.org/10.1007/8904_2018_110

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  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-58613-6

  • Online ISBN: 978-3-662-58614-3

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