Browse

Directly converted patient-specific induced neurons mirror the neuropathology of FUS with disrupted nuclear localization in amyotrophic lateral sclerosis

Cited 0 time in Web of Science Cited 0 time in Scopus
Authors
Lim, Su Min; Choi, Won Jun; Oh, Ki-Wook; Xue, Yuanchao; Choi, Ji Young; Kim, Sung Hoon; Nahm, Minyeop; Kim, Young-Eun; Lee, Jinhyuk; Noh, Min-Young; Lee, Seungbok; Hwang, Sejin; Ki, Chang-Seok; Fu, Xiang-Dong; Kim, Seung Hyun
Issue Date
2016-01-22
Publisher
BioMed Central
Citation
Molecular Neurodegeneration, 11(1):8
Keywords
Amyotrophic lateral sclerosisFused in sarcomaHuman cell modelsInduced neuronNuclear localization signalStress granulesNeuronal cytoplasmic inclusion
Abstract
Background
Mutations in the fused in sarcoma (FUS) gene have been linked to amyotrophic lateral sclerosis (ALS). ALS patients with FUS mutations exhibit neuronal cytoplasmic mislocalization of the mutant FUS protein. ALS patients fibroblasts or induced pluripotent stem cell (iPSC)-derived neurons have been developed as models for understanding ALS-associated FUS (ALS-FUS) pathology; however, pathological neuronal signatures are not sufficiently present in the fibroblasts of patients, whereas the generation of iPSC-derived neurons from ALS patients requires relatively intricate procedures.

Results
Here, we report the generation of disease-specific induced neurons (iNeurons) from the fibroblasts of patients who carry three different FUS mutations that were recently identified by direct sequencing and multi-gene panel analysis. The mutations are located at the C-terminal nuclear localization signal (NLS) region of the protein (p.G504Wfs*12, p.R495*, p.Q519E): two de novo mutations in sporadic ALS and one in familial ALS case. Aberrant cytoplasmic mislocalization with nuclear clearance was detected in all patient-derived iNeurons, and oxidative stress further induced the accumulation of cytoplasmic FUS in cytoplasmic granules, thereby recapitulating neuronal pathological features identified in mutant FUS (p.G504Wfs*12)-autopsied ALS patient. Importantly, such FUS pathological hallmarks of the patient with the p.Q519E mutation were only detected in patient-derived iNeurons, which contrasts to predominant FUS (p.Q519E) in the nucleus of both the transfected cells and patient-derived fibroblasts.

Conclusions
Thus, iNeurons may provide a more reliable model for investigating FUS mutations with disrupted NLS for understanding FUS-associated proteinopathies in ALS.
Language
English
URI
https://hdl.handle.net/10371/109843
Files in This Item:
Appears in Collections:
College of Natural Sciences (자연과학대학)Brain and Cognitive Sciences (뇌인지과학과)Journal Papers (저널논문_뇌인지과학과)
  • mendeley

Items in S-Space are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse