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Cited by 174Down syndrome and intellectual disability researchGenetics and Neurodevelopmental DisordersAlzheimer's disease research and treatments

Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome

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Voronov, Sergey V., Frere, Samuel G., Giovedi, Silvia, Pollina, Elizabeth A., Borel, Christelle, Zhang, Hong, Schmidt, Cecilia, Akeson, Ellen C. +8 more·2008·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0803756105PMC PMC2453748
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Abstract

Phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P 2 ] is a signaling phospholipid implicated in a wide variety of cellular functions. At synapses, where normal PtdIns(4,5)P 2 balance is required for proper neurotransmission, the phosphoinositide phosphatase synaptojanin 1 is a key regulator of its metabolism. The underlying gene, SYNJ1 , maps to human chromosome 21 and is thus a candidate for involvement in Down's syndrome (DS), a complex disorder resulting from the overexpression of trisomic genes. Here, we show that PtdIns(4,5)P 2 metabolism is altered in the brain of Ts65Dn mice, the most commonly used model of DS. This defect is rescued by restoring Synj1 to disomy in Ts65Dn mice and is recapitulated in transgenic mice overexpressing Synj1 from BAC constructs. These transgenic mice also exhibit deficits in performance of the Morris water maze task, suggesting that PtdIns(4,5)P 2 dyshomeostasis caused by gene dosage imbalance for Synj1 may contribute to brain dysfunction and cognitive disabilities in DS.

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Authors
Voronov, S. V., Frere, S. G., Giovedi, S., Pollina, E. A., Borel, C., Zhang, H., Schmidt, C., Akeson, E. C., Wenk, M. R., Cimasoni, L., Arancio, O., Davisson, M. T., Antonarakis, S. E., Gardiner, K., De Camilli, P., & Di Paolo, G.
Affiliations
  • Columbia University Irving Medical Center (US)
  • *Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032;
  • Department of Cell Biology, Howard Hughes Medical Institute, Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT 06510;
  • University of Geneva (CH)
  • Jackson Laboratory (US)
  • National University of Singapore (SG)
  • University of Colorado Anschutz (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2008-07-08
Volume
105
Issue
27
Pages
9415-9420
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0803756105
PMC
PMC2453748
OpenAlex
W2073700418
Cited by
174
References
4
Citations by year
2026: 3 · 2025: 8 · 2024: 1 · 2023: 6 · 2022: 6 · 2021: 9 · 2020: 11 · 2019: 10 · 2018: 6 · 2017: 6 · 2016: 10 · 2015: 9 · 2014: 15 · 2013: 10 · 2012: 23
FWCI
13.58
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • National University of Singapore (submittedVersion)
  • CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
Funders
  • National Science Foundation
  • March of Dimes Foundation
  • McKnight Foundation
  • European Commission
  • National University of Singapore
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
  • National Institutes of Health
  • Biomedical Research Council
  • National Institute on Drug Abuse (P30DA018343)
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
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
SYNJ1, phosphatidylinositol 4,5-bisphosphate, phosphoinositide metabolism, Down syndrome, Ts65Dn mouse model, gene dosage imbalance, cognitive impairment, synaptic function, phosphoinositide phosphatase, BAC transgenic mice
MeSH terms
Phosphoinositide 5-Phosphatases, Animals, Brain, Cognition Disorders, Disease Models, Animal, Down Syndrome, Homeostasis, Learning, Male, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Phosphoric Monoester Hydrolases, Gene Dosage, Maze Learning, Phosphatidylinositol 4,5-Diphosphate, Mice

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