Article open access publication

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

Stem Cell Reports, Elsevier, ISSN 2213-6711

Volume 8, 3, 2017

DOI:10.1016/j.stemcr.2017.01.012, Dimensions: pub.1083849234, PMC: PMC5355623, PMID: 28216144,

Affiliations

Organisations

  1. (1) University of Copenhagen, grid.5254.6, KU
  2. (2) Bioneer (Denmark), grid.424169.c
  3. (3) University of Southern Denmark, grid.10825.3e, SDU
  4. (4) Lundbeck (Denmark), grid.424580.f
  5. (5) Neurogenetics Clinic Research Lab, Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
  6. (6) Beijing Genomics Institute, grid.21155.32
  7. (7) Aarhus University, grid.7048.b, AU

Countries

Denmark

China

Continents

Europe

Asia

Description

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.

Funders

Research Categories

Main Subject Area

Links & Metrics

NORA University Profiles

University of Copenhagen

University of Southern Denmark

Aarhus University

Danish Open Access Indicator

2017: Realized

Research area: Medicine

Dimensions Citation Indicators

Times Cited: 33

Field Citation Ratio (FCR): 8.86

Relative Citation ratio (RCR): 1.64

Open Access Info

Pure Gold