Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration

Sheona Watson-Scales; Bernadett Kalmar; Eva Lana-Elola; Dorota Gibbins; Federica La Russa; Frances Wiseman; Matthew Williamson; Rachele Saccon; Amy Slender; Anna Olerinyova; Radma Mahmood; Emma Nye; Heather Cater; Sara Wells; Y. Eugene Yu; David L.H. Bennett; Linda Greensmith; Elizabeth M.C. Fisher; Victor L.J. Tybulewicz

doi:10.1371/journal.pgen.1007383

Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration

Sheona Watson-Scales, Bernadett Kalmar, Eva Lana-Elola, Dorota Gibbins, Federica La Russa, Frances Wiseman, Matthew Williamson, Rachele Saccon, Amy Slender, Anna Olerinyova, Radma Mahmood, Emma Nye, Heather Cater, Sara Wells, Y. Eugene Yu, David L.H. Bennett, Linda Greensmith, Elizabeth M.C. Fisher, Victor L.J. Tybulewicz^*

^*Corresponding author for this work

Wolfson SPaRC

Research output: Contribution to journal › Article › peer-review

24 Citations (Scopus)

Abstract

Down Syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and results in a spectrum of phenotypes including learning and memory deficits, and motor dysfunction. It has been hypothesized that an additional copy of a few Hsa21 dosage-sensitive genes causes these phenotypes, but this has been challenged by observations that aneuploidy can cause phenotypes by the mass action of large numbers of genes, with undetectable contributions from individual sequences. The motor abnormalities in DS are relatively understudied—the identity of causative dosage-sensitive genes and the mechanism underpinning the phenotypes are unknown. Using a panel of mouse strains with duplications of regions of mouse chromosomes orthologous to Hsa21 we show that increased dosage of small numbers of genes causes locomotor dysfunction and, moreover, that the Dyrk1a gene is required in three copies to cause the phenotype. Furthermore, we show for the first time a new DS phenotype: loss of motor neurons both in mouse models and, importantly, in humans with DS, that may contribute to locomotor dysfunction.

Original language	English
Article number	e1007383
Journal	PLoS Genetics
Volume	14
Issue number	5
DOIs	https://doi.org/10.1371/journal.pgen.1007383
Publication status	Published - 10 May 2018

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Watson-Scales, S., Kalmar, B., Lana-Elola, E., Gibbins, D., La Russa, F., Wiseman, F., Williamson, M., Saccon, R., Slender, A., Olerinyova, A., Mahmood, R., Nye, E., Cater, H., Wells, S., Yu, Y. E., Bennett, D. L. H., Greensmith, L., Fisher, E. M. C., & Tybulewicz, V. L. J. (2018). Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration. PLoS Genetics, 14(5), Article e1007383. https://doi.org/10.1371/journal.pgen.1007383

@article{881d7f58ba9e4ad8b7427bed8537c8b5,

title = "Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration",

abstract = "Down Syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and results in a spectrum of phenotypes including learning and memory deficits, and motor dysfunction. It has been hypothesized that an additional copy of a few Hsa21 dosage-sensitive genes causes these phenotypes, but this has been challenged by observations that aneuploidy can cause phenotypes by the mass action of large numbers of genes, with undetectable contributions from individual sequences. The motor abnormalities in DS are relatively understudied—the identity of causative dosage-sensitive genes and the mechanism underpinning the phenotypes are unknown. Using a panel of mouse strains with duplications of regions of mouse chromosomes orthologous to Hsa21 we show that increased dosage of small numbers of genes causes locomotor dysfunction and, moreover, that the Dyrk1a gene is required in three copies to cause the phenotype. Furthermore, we show for the first time a new DS phenotype: loss of motor neurons both in mouse models and, importantly, in humans with DS, that may contribute to locomotor dysfunction.",

author = "Sheona Watson-Scales and Bernadett Kalmar and Eva Lana-Elola and Dorota Gibbins and {La Russa}, Federica and Frances Wiseman and Matthew Williamson and Rachele Saccon and Amy Slender and Anna Olerinyova and Radma Mahmood and Emma Nye and Heather Cater and Sara Wells and Yu, {Y. Eugene} and Bennett, {David L.H.} and Linda Greensmith and Fisher, {Elizabeth M.C.} and Tybulewicz, {Victor L.J.}",

year = "2018",

month = may,

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doi = "10.1371/journal.pgen.1007383",

language = "English",

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Watson-Scales, S, Kalmar, B, Lana-Elola, E, Gibbins, D, La Russa, F, Wiseman, F, Williamson, M, Saccon, R, Slender, A, Olerinyova, A, Mahmood, R, Nye, E, Cater, H, Wells, S, Yu, YE, Bennett, DLH, Greensmith, L, Fisher, EMC & Tybulewicz, VLJ 2018, 'Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration', PLoS Genetics, vol. 14, no. 5, e1007383. https://doi.org/10.1371/journal.pgen.1007383

TY - JOUR

T1 - Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration

AU - Watson-Scales, Sheona

AU - Kalmar, Bernadett

AU - Lana-Elola, Eva

AU - Gibbins, Dorota

AU - La Russa, Federica

AU - Wiseman, Frances

AU - Williamson, Matthew

AU - Saccon, Rachele

AU - Slender, Amy

AU - Olerinyova, Anna

AU - Mahmood, Radma

AU - Nye, Emma

AU - Cater, Heather

AU - Wells, Sara

AU - Yu, Y. Eugene

AU - Bennett, David L.H.

AU - Greensmith, Linda

AU - Fisher, Elizabeth M.C.

AU - Tybulewicz, Victor L.J.

PY - 2018/5/10

Y1 - 2018/5/10

N2 - Down Syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and results in a spectrum of phenotypes including learning and memory deficits, and motor dysfunction. It has been hypothesized that an additional copy of a few Hsa21 dosage-sensitive genes causes these phenotypes, but this has been challenged by observations that aneuploidy can cause phenotypes by the mass action of large numbers of genes, with undetectable contributions from individual sequences. The motor abnormalities in DS are relatively understudied—the identity of causative dosage-sensitive genes and the mechanism underpinning the phenotypes are unknown. Using a panel of mouse strains with duplications of regions of mouse chromosomes orthologous to Hsa21 we show that increased dosage of small numbers of genes causes locomotor dysfunction and, moreover, that the Dyrk1a gene is required in three copies to cause the phenotype. Furthermore, we show for the first time a new DS phenotype: loss of motor neurons both in mouse models and, importantly, in humans with DS, that may contribute to locomotor dysfunction.

AB - Down Syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and results in a spectrum of phenotypes including learning and memory deficits, and motor dysfunction. It has been hypothesized that an additional copy of a few Hsa21 dosage-sensitive genes causes these phenotypes, but this has been challenged by observations that aneuploidy can cause phenotypes by the mass action of large numbers of genes, with undetectable contributions from individual sequences. The motor abnormalities in DS are relatively understudied—the identity of causative dosage-sensitive genes and the mechanism underpinning the phenotypes are unknown. Using a panel of mouse strains with duplications of regions of mouse chromosomes orthologous to Hsa21 we show that increased dosage of small numbers of genes causes locomotor dysfunction and, moreover, that the Dyrk1a gene is required in three copies to cause the phenotype. Furthermore, we show for the first time a new DS phenotype: loss of motor neurons both in mouse models and, importantly, in humans with DS, that may contribute to locomotor dysfunction.

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DO - 10.1371/journal.pgen.1007383

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VL - 14

JO - PLoS Genetics

JF - PLoS Genetics

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Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration

Abstract

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