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

Molecular Neurodegeneration
Su Min LimSeung Hyun Kim

Abstract

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. 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...Continue Reading

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Citations

Nov 11, 2016·Nature·J Paul TaylorDon W Cleveland
May 29, 2016·Cell and Tissue Research·John T WalkerDouglas W Hamilton
Mar 15, 2020·Journal of Neuroscience Research·Gary X D'SouzaJessica E Young
Aug 30, 2019·Molecular Neurodegeneration·Jenny DoEllen Sidransky
Oct 17, 2017·Frontiers in Neuroscience·Janelle Drouin-OuelletMalin Parmar
Dec 24, 2019·Frontiers in Neuroscience·Rita MejziniP Anthony Akkari
Oct 23, 2020·Science Translational Medicine·Minyeop NahmSeung Hyun Kim
Nov 19, 2020·Diseases·Irene Villalón-GarcíaJosé Antonio Sánchez-Alcázar
Jul 13, 2021·Frontiers in Aging Neuroscience·Mohammad Reza AsadiMaryam Rezazadeh

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Methods Mentioned

BETA
dissecting
biopsy
confocal microscopy
electrophoresis

Software Mentioned

CHARMM
iNeuron
Jmol

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