TY - JOUR
T1 - Reversal of pathology in CHMP2B-mediated frontotemporal dementia patient cells using RNA interference
AU - Nielsen, Troels Tolstrup
AU - Mizielinska, Sarah
AU - Hasholt, Lis
AU - Isaacs, Adrian M
AU - Nielsen, Jørgen E
AU - the FReJA Consortium
N1 - Copyright © 2012 John Wiley & Sons, Ltd.
PY - 2012/8
Y1 - 2012/8
N2 - Background: Frontotemporal dementia is the second most common form of young-onset dementia after Alzheimer's disease, and several genetic forms of frontotemporal dementia are known. A rare genetic variant is caused by a point mutation in the CHMP2B gene. CHMP2B is a component of the ESCRT-III complex, which is involved in endosomal trafficking of proteins targeted for degradation in lysosomes. Mutations in CHMP2B result in abnormal endosomal structures in patient fibroblasts and patient brains, probably through a gain-of-function mechanism, suggesting that the endosomal pathway plays a central role in the pathogenesis of the disease. Methods: In the present study, we used lentiviral vectors to efficiently knockdown CHMP2B by delivering microRNA embedded small hairpin RNAs. Results: We show that CHMP2B can be efficiently knocked down in patient fibroblasts using an RNA interference approach and that the knockdown causes reversal of the abnormal endosomal phenotype observed in patient fibroblasts. Conclusions: This is the first description of a treatment that reverses the cellular pathology caused by mutant CHMP2B and suggests that RNA interference might be a feasible therapeutic strategy. Furthermore, it provides the first proof of a direct link between the disease-causing mutation and the cellular phenotype in cells originating from CHMP2B mutation patients.
AB - Background: Frontotemporal dementia is the second most common form of young-onset dementia after Alzheimer's disease, and several genetic forms of frontotemporal dementia are known. A rare genetic variant is caused by a point mutation in the CHMP2B gene. CHMP2B is a component of the ESCRT-III complex, which is involved in endosomal trafficking of proteins targeted for degradation in lysosomes. Mutations in CHMP2B result in abnormal endosomal structures in patient fibroblasts and patient brains, probably through a gain-of-function mechanism, suggesting that the endosomal pathway plays a central role in the pathogenesis of the disease. Methods: In the present study, we used lentiviral vectors to efficiently knockdown CHMP2B by delivering microRNA embedded small hairpin RNAs. Results: We show that CHMP2B can be efficiently knocked down in patient fibroblasts using an RNA interference approach and that the knockdown causes reversal of the abnormal endosomal phenotype observed in patient fibroblasts. Conclusions: This is the first description of a treatment that reverses the cellular pathology caused by mutant CHMP2B and suggests that RNA interference might be a feasible therapeutic strategy. Furthermore, it provides the first proof of a direct link between the disease-causing mutation and the cellular phenotype in cells originating from CHMP2B mutation patients.
U2 - 10.1002/jgm.2649
DO - 10.1002/jgm.2649
M3 - Journal article
C2 - 22786763
SN - 1099-498X
VL - 14
SP - 521
EP - 529
JO - Journal of Gene Medicine
JF - Journal of Gene Medicine
IS - 8
ER -