Analysis of motor dysfunction in down Syndrome reveals motor neuron degeneration.
Open accessAbstract
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 summaryDown Syndrome is caused by an extra copy of chromosome 21 and results in many different phenotypes including learning difficulties, Alzheimer's disease and problems with motor function such as abnormal gait and poor fine motor skills.These different phenotypes are thought to result from an increased copy of one more of the genes on chromosome 21, but it is not known which gene or genes cause the phenotypes.Using a panel of mouse strains with an extra copy of different sets of mouse genes that are equivalent to the
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A decrease in choline acetyltransferase (ChAT)-positive motor neurons was identified in cervical sections of the spinal cord from older adults with Down syndrome (58-70 years).
“A decrease in choline acetyltransferase (ChAT)-positive motor neurons was identified in cervical sections of the spinal cord from older adults with DS (58–70 years) (Watson-Scales et al., 2018).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Watson-Scales et al., 2018
The Results section reports fewer motor neurons in cervical spinal cord sections from adults with Down syndrome than in controls, and the human-autopsy Methods give the participants’ ages as 58–70 years. However, the Methods say the researchers counted neurons with intense Nissl staining; they do not identify the counted cells as ChAT-positive. (LLM, conf=0.90)
Experimental — accuracy not yet measuredDp(16)1Yey show no change in brain volume, NPC proliferation, neurogenesis, or neuronal density in the developing forebrain; Dp1Tyb show no changes in cerebellar anatomy.
“No change in brain volume, NPC proliferation, neurogenesis, or neuronal density was identified in the developing forebrain (Goodliffe et al., 2016) nor any changes in cerebellar anatomy in Dp1Tyb (Watson-Scales et al., 2018).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Watson-Scales et al., 2018
The Results section, “No alteration in cerebellar anatomy in Dp(16)1Yey mice” (page unavailable), reports no significant anatomical changes in Dp(16)1Yey cerebella. The citing sentence attributes that finding to Dp1Tyb, a different mouse line; the cited paper does not report the same anatomical analysis for Dp1Tyb. The forebrain clause is attached to a different citation and is not judged here. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDp1Tyb shows a decrease in motor neurons in the spinal cord at six months of age, same as aged Ts65Dn and humans.
“Additionally, Dp1Tyb shows the same decrease in motor neurons in the spinal cord at six month of age that has been observed in aged Ts65Dn and humans (Watson-Scales et al., 2018).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Watson-Scales et al., 2018
The Results (Fig. 6; page unavailable) report reduced spinal motor-neuron numbers in Tc1 and Dp(16)1Yey mice, including measurements at six months, while the human Results report reduced numbers in adults with Down syndrome. The cited paper discusses Dp1Tyb in its sensory-function Results, but does not report a six-month spinal motor-neuron decrease in Dp1Tyb or establish the claimed comparison with aged Ts65Dn mice. (LLM, conf=0.88)
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“Additionally, Dp1Tyb shows the same decrease in motor neurons in the spinal cord at six month of age that has been observed in aged Ts65Dn and humans (Watson-Scales et al., 2018).”
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Couto, M. D. M., de Oliveira, J., Fulan, A. L. D. A., Antunes, L. C. D. O., Delambert, C. H. L., Goldberg, T. B. L., Corrente, J. E., Prearo, A. Y., & da Fonseca, C. R. B. (2022) · International Journal of Health Science · doi:10.22533/at.ed.1592402219072
An Exploration of the Effects of Gene-Editing Technology on Human Identity
Allwardt, A. E. (2023) · Voices in Bioethics · doi:10.52214/vib.v9i.11794
DYRK1A kinase triplication is the major cause of Otitis Media in Down SyndromePreprint
Tateossian, H., Southern, A., Vikhe, P. P., Lana‐Elola, E., Watson-Scales, S., Gibbins, D., Williams, D. J., Purnell, T., Mburu, P., Parker, A., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.10.03.616443
Self-citationDYRK1A kinase triplication is the major cause of Otitis Media in Down SyndromePreprint
Tateossian, H., Southern, A., Vikhe, P. P., Lana‐Elola, E., Watson-Scales, S., Gibbins, D., Williams, D. J., Purnell, T., Mburu, P., Parker, A., et al. (2025) · eLife · doi:10.7554/elife.101969
Self-citationUsing Drosophila to Study the Mechanisms That Underlie Down Syndrome
Ye, B. (2025) · Springer eBooks · doi:10.1007/978-3-031-78611-2_5
Folz, A., Sloan, K., & Roper, R. J. (2025) · Springer eBooks · doi:10.1007/978-3-031-78611-2_1
Impact of Cre/LoxP-Mediated Chromosome Engineering Technology on Down Syndrome Research
Xing, Z., Douglas, A., Pao, A., Glass, T. J., Connor, N. P., & Yu, Y. E. (2025) · Springer eBooks · doi:10.1007/978-3-031-78611-2_2
Self-citationCraniofacial analysis of Down syndrome rodent models
Saavedra, J. T. A. (2024) · doi:10.70675/064b45abz323ez478ez93ddz8ce0747170c2
Jiang, X., Liu, C., Xing, Z., Li, Y., Douglas, A., Gao, L., Pao, A., Silverman, J., & Yu, E. Y. (2026) · G3 Genes Genomes Genetics · doi:10.1093/g3journal/jkag173
- Authors
- 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.
- Affiliations
- The Francis Crick Institute (GB)
- UCL Queen Square Institute of Neurology (GB)
- Mary Lyon Centre at MRC Harwell (GB)
- Roswell Park Comprehensive Cancer Center (US)
- University of Oxford (GB)
- Corresponding author
- Fisher, Elizabeth M. C.
- Tybulewicz, Victor L. J.
- ORCID
- Venue
- PLOS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2018-05-10
- Volume
- 14
- Issue
- 5
- Pages
- e1007383
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC5963810
- OpenAlex
- W2802259607
- Cited by
- 45
- References
- 48
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 6 · 2023: 6 · 2022: 8 · 2021: 5 · 2020: 3 · 2019: 4 · 2018: 1
- FWCI
- 3.10
- Type
- journal article
- Language
- en
- Update notices
- new_version (2018-05-22)
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (080174, 098327, 098328)
- Medical Research Council (U117527252)
- Francis Crick Institute (FC001194)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
- Keywords
- Down syndrome, motor impairment, motor neuron degeneration, DYRK1A, dosage-sensitive genes, gene dosage, locomotor dysfunction, chromosome 21
- MeSH terms
- Dyrk Kinases, Adult, Aged, Animals, Autopsy, Disease Models, Animal, Down Syndrome, Humans, Male, Mice, Inbred C57BL, Middle Aged, Motor Activity, Motor Neurons, Nerve Degeneration, Protein-Tyrosine Kinases, Spinal Cord, Gene Expression, Protein Serine-Threonine Kinases, Mice, Knockout
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