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

Abstract

SummaryThe 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.

Endolysosomal degradation of Tau and its role in glucocorticoid‐driven hippocampal malfunction

“…Recent evidence suggests that dysfunction of the ESCRT machinery itself is associated with profound cytopathology, as brain‐specific deletion of ESCRT components in mice leads to the accumulation of ubiquitylated proteins, impaired endosomal trafficking, and cell death (Watson et al , ; Oshima et al , ). Further, a truncating mutation in ESCRT‐III protein CHMP2b causes familial frontotemporal dementia and amyotrophic lateral sclerosis, and at the cellular level induces endolysosomal pathway dysfunction and the accumulation of ubiquitylated proteins (Clayton et al , ; Zhang et al , ). Together with our findings, the above studies support the importance of the endolysosomal pathway, and specifically the ESCRT machinery, in clearance of ubiquitylated proteins such as Tau.…”

Endolysosomal degradation of Tau and its role in glucocorticoid-driven hippocampal malfunction

“…Recent evidence suggests that dysfunction of the ESCRT machinery itself is associated with profound cytopathology, as brain-specific deletion of ESCRT components in mice leads to the accumulation of ubiquitylated proteins, impaired endosomal trafficking, and cell death (Oshima, Hasegawa et al, 2016, Watson, Bhattacharyya et al, 2015. Further, a truncating mutation in ESCRT-III protein CHMP2b causes familial frontotemporal dementia and amyotrophic lateral sclerosis, and at the cellular level induces endo-lysosomal pathway dysfunction and the accumulation of ubiquitylated proteins (Clayton, Mizielinska et al, 2015, Zhang, Schmid et al, 2017. Together with our findings, the above studies support the importance of the endo-lysosomal pathway, and specifically the ESCRT machinery, in the clearance of ubiquitylated proteins such as Tau.…”

“…Recent evidence suggests that dysfunction of the ESCRT machinery itself is associated with profound cytopathology, as brain-specific deletion of ESCRT components in mice leads to the accumulation of ubiquitylated proteins, impaired endosomal trafficking, and cell death 41,42 . Further, a truncating mutation in ESCRT-III protein CHMP2b causes familial frontotemporal dementia and amyotrophic lateral sclerosis, and at the cellular level induces endo-lysosomal pathway dysfunction and the accumulation of ubiquitylated proteins 43,44 . Together with our findings, the above studies Multiple cellular pathways are altered by chronic stress, increasing the vulnerability of affected individuals to psychiatric and neurodegenerative diseases such as depression and AD 47,48 .…”

Neuroprotective potential of astroglia

“…Human‐induced pluripotent stem cell (hiPSC)‐derived neurons currently attract a lot of attention as invaluable tools for modeling disease and as potential means of therapy (An et al, ; Israel et al, ; Chen et al, ; Zhang et al, ). HiPSCs provide an unlimited source of genetically personalized cells of various phenotypes, including neurons with a diminished risk of immunorejection (Grskovic et al, ; Ichida and Kiskinis, ).…”