Down syndrome is a metabolic disease: altered insulin signaling mediates peripheral and brain dysfunctions

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  • dc.contributor.author Dierssen, Mara
  • dc.contributor.author Fructuoso, Marta
  • dc.contributor.author Martínez de Lagrán Cabredo, María
  • dc.contributor.author Perluigi, Marzia
  • dc.contributor.author Barone, Eugenio
  • dc.date.accessioned 2020-10-20T06:02:03Z
  • dc.date.available 2020-10-20T06:02:03Z
  • dc.date.issued 2020
  • dc.description.abstract Down syndrome (DS) is the most frequent chromosomal abnormality that causes intellectual disability, resulting from the presence of an extra complete or segment of chromosome 21 (HSA21). In addition, trisomy of HSA21 contributes to altered energy metabolism that appears to be a strong determinant in the development of pathological phenotypes associated with DS. Alterations include, among others, mitochondrial defects, increased oxidative stress levels, impaired glucose, and lipid metabolism, finally resulting in reduced energy production and cellular dysfunctions. These molecular defects seem to account for a high incidence of metabolic disorders, i.e., diabetes and/or obesity, as well as a higher risk of developing Alzheimer's disease (AD) in DS. A dysregulation of the insulin signaling with reduced downstream pathways represents a common pathophysiological aspect in the development of both peripheral and central alterations leading to diabetes/obesity and AD. This is further strengthened by evidence showing that the molecular mechanisms responsible for such alterations appear to be similar between peripheral organs and brain. Considering that DS subjects are at high risk to develop either peripheral or brain metabolic defects, this review will discuss current knowledge about the link between trisomy of HSA21 and defects of insulin and insulin-related pathways in DS. Drawing the molecular signature underlying these processes in DS is a key challenge to identify novel drug targets and set up new prevention strategies aimed to reduce the impact of metabolic disorders and cognitive decline.
  • dc.description.sponsorship This work was supported by Fondi Ateneo grant funded by the Sapienza University n° RM11715C77336E99 to EB and n° C26H15JT9X to MP, Fondation Jérôme Lejeune (2019b – Project #1887) to EB; Fondation Jérôme Lejeune, MINECO (SAF2016-79956-R), H2020 SC1, GO-DS21- 848077, CDTI (“Smartfoods”), Fundació La Marató De TV3 (201620-31_MDierssen), and JPND HEROES (tHE cRossroad Of dEmentia Syndromes to MD). The CRG was a Center of Excellence Severo Ochoa SEV-2016-0571.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Dierssen M, Fructuoso M, Martínez de Lagrán M, Perluigi M, Barone E. Down syndrome is a metabolic disease: altered insulin signaling mediates peripheral and brain dysfunctions. Front Neurosci. 2020; 14:670. DOI: 10.3389/fnins.2020.00670
  • dc.identifier.doi http://dx.doi.org/10.3389/fnins.2020.00670
  • dc.identifier.issn 1662-4548
  • dc.identifier.uri http://hdl.handle.net/10230/45519
  • dc.language.iso eng
  • dc.publisher Frontiers
  • dc.relation.ispartof Front Neurosci. 2020; 14:670
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/848077
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-79956-R
  • dc.rights © 2020 Dierssen, Fructuoso, Martínez de Lagrán, Perluigi and Barone. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Down syndrome
  • dc.subject.keyword Brain insulin resistance
  • dc.subject.keyword Insulin
  • dc.subject.keyword Meatbolic disroders
  • dc.subject.keyword Metabolism
  • dc.title Down syndrome is a metabolic disease: altered insulin signaling mediates peripheral and brain dysfunctions
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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