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Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Transient p53 suppression increases reprogramming of human fibroblasts without affecting apoptosis and DNA damage

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Mesenchymal stromal cell phenotype is not influenced by confluence during culture expansion

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Paroxysmal Cranial Dyskinesia and Nail-Patella Syndrome Caused by a Novel Variant in the LMX1B Gene

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Enhancement of Autophagy and Solubilization of Ataxin-2 Alleviate Apoptosis in Spinocerebellar Ataxia Type 2 Patient Cells

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • Chen-Yu Zhang
  • Benjamin Schmid
  • Nanett K Nikolaisen
  • Mikkel Aabech Rasmussen
  • Blanca I Aldana
  • Mikkel Agger
  • Kirstine Calloe
  • Tina C Stummann
  • Hjalte M Larsen
  • Troels T Nielsen
  • Jinrong Huang
  • Fengping Xu
  • Xin Liu
  • Lars Bolund
  • Morten Meyer
  • Lasse K Bak
  • Helle S Waagepetersen
  • Yonglun Luo
  • Jørgen E Nielsen
  • Bjørn Holst
  • Christian Clausen
  • Poul Hyttel
  • Kristine K Freude
  • FReJA Consortium
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The truncated mutant form of the charged multivesicular body protein 2B (CHMP2B) is causative for frontotemporal dementia linked to chromosome 3 (FTD3). CHMP2B is a constituent of the endosomal sorting complex required for transport (ESCRT) and, when mutated, disrupts endosome-to-lysosome trafficking and substrate degradation. To understand the underlying molecular pathology, FTD3 patient induced pluripotent stem cells (iPSCs) were differentiated into forebrain-type cortical neurons. FTD3 neurons exhibited abnormal endosomes, as previously shown in patients. Moreover, mitochondria of FTD3 neurons displayed defective cristae formation, accompanied by deficiencies in mitochondrial respiration and increased levels of reactive oxygen. In addition, we provide evidence for perturbed iron homeostasis, presenting an in vitro patient-specific model to study the effects of iron accumulation in neurodegenerative diseases. All phenotypes observed in FTD3 neurons were rescued in CRISPR/Cas9-edited isogenic controls. These findings illustrate the relevance of our patient-specific in vitro models and open up possibilities for drug target development.

OriginalsprogEngelsk
TidsskriftStem Cell Reviews and Reports
Vol/bind8
Udgave nummer3
Sider (fra-til)648-658
Antal sider11
ISSN1550-8943
DOI
StatusUdgivet - 14 mar. 2017

ID: 51500951