Evaluation of disease lesions in the developing canine MPS IIIA brain

Leanne K. Winner, Neil R. Marshall, Robert D. Jolly, Paul J. Trim, Stephen K. Duplock, Marten F. Snel, Kim M. Hemsley

Research output: Chapter in Book/Report/Conference proceedingChapter

1 Citation (Scopus)

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.

LanguageEnglish
Title of host publicationJIMD Reports
PublisherSpringer
Pages91-101
Number of pages11
DOIs
Publication statusPublished - 20 Jun 2018

Publication series

NameJIMD Reports
Volume43
ISSN (Print)2192-8304
ISSN (Electronic)2192-8312

Keywords

  • Brain development
  • Dog
  • Ganglioside
  • Heparan sulphate
  • Lysosome
  • Microglia
  • Mucopolysaccharidosis
  • Neuroinflammation

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

Cite this

Winner, L. K., Marshall, N. R., Jolly, R. D., Trim, P. J., Duplock, S. K., Snel, M. F., & Hemsley, K. M. (2018). Evaluation of disease lesions in the developing canine MPS IIIA brain. In JIMD Reports (pp. 91-101). (JIMD Reports; Vol. 43). Springer. https://doi.org/10.1007/8904_2018_110
Winner, Leanne K. ; Marshall, Neil R. ; Jolly, Robert D. ; Trim, Paul J. ; Duplock, Stephen K. ; Snel, Marten F. ; Hemsley, Kim M. / Evaluation of disease lesions in the developing canine MPS IIIA brain. JIMD Reports. Springer, 2018. pp. 91-101 (JIMD Reports).
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Winner, LK, Marshall, NR, Jolly, RD, Trim, PJ, Duplock, SK, Snel, MF & Hemsley, KM 2018, Evaluation of disease lesions in the developing canine MPS IIIA brain. in JIMD Reports. JIMD Reports, vol. 43, Springer, pp. 91-101. https://doi.org/10.1007/8904_2018_110

Evaluation of disease lesions in the developing canine MPS IIIA brain. / Winner, Leanne K.; Marshall, Neil R.; Jolly, Robert D.; Trim, Paul J.; Duplock, Stephen K.; Snel, Marten F.; Hemsley, Kim M.

JIMD Reports. Springer, 2018. p. 91-101 (JIMD Reports; Vol. 43).

Research output: Chapter in Book/Report/Conference proceedingChapter

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T1 - Evaluation of disease lesions in the developing canine MPS IIIA brain

AU - Winner, Leanne K.

AU - Marshall, Neil R.

AU - Jolly, Robert D.

AU - Trim, Paul J.

AU - Duplock, Stephen K.

AU - Snel, Marten F.

AU - Hemsley, Kim M.

PY - 2018/6/20

Y1 - 2018/6/20

N2 - 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.

AB - 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.

KW - Brain development

KW - Dog

KW - Ganglioside

KW - Heparan sulphate

KW - Lysosome

KW - Microglia

KW - Mucopolysaccharidosis

KW - Neuroinflammation

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U2 - 10.1007/8904_2018_110

DO - 10.1007/8904_2018_110

M3 - Chapter

T3 - JIMD Reports

SP - 91

EP - 101

BT - JIMD Reports

PB - Springer

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Winner LK, Marshall NR, Jolly RD, Trim PJ, Duplock SK, Snel MF et al. Evaluation of disease lesions in the developing canine MPS IIIA brain. In JIMD Reports. Springer. 2018. p. 91-101. (JIMD Reports). https://doi.org/10.1007/8904_2018_110