Neurons Induced From Fibroblasts of c9ALS/FTD Patients Reproduce the Pathology Seen in the Central Nervous System

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative conditions. A non-coding hexanucleotide (GGGGCC) repeat expansion in the c9orf72 gene is the most common genetic cause c9ALS/FTD. We present a cellular model of c9ALS/FTD where induced neurons (iNeu...

Full description

Saved in:
Bibliographic Details
Published in:Frontiers in neuroscience 2019-09, Vol.13, p.935-935
Main Authors: Bauer, Peter O., Dunmore, Judith H., Sasaguri, Hiroki, Matoska, Vaclav
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
Antisense oligonucleotides
Antisense therapy
c9ALS/FTD
c9orf72 expansion
Cell viability
Central nervous system
Dementia
Dementia disorders
Disease
Fibroblasts
Frontotemporal dementia
induced neurons
iNeurons
Neurodegeneration
Neurogenesis
Neurons
Neuroscience
Non-coding RNA
Oligonucleotides
Pathology
Patients
Proteins
Ribonucleic acid
RNA
RNA foci
Skin
Stem cells
Transcription
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative conditions. A non-coding hexanucleotide (GGGGCC) repeat expansion in the c9orf72 gene is the most common genetic cause c9ALS/FTD. We present a cellular model of c9ALS/FTD where induced neurons (iNeurons) are generated within two weeks by direct conversion of patients` dermal fibroblasts through down-regulation of polypyrimidine-tract-binding protein 1 (PTB1). While sense (S) and anti-sense (AS) intranuclear RNA foci were observed in both fibroblasts and iNeurons, the accumulation of (S) and (AS) repeat-associated non-ATG translation (RANT) products were detected only in iNeurons. Importantly, anti-sense oligonucleotides (ASOs) against the (S) repeat transcript lead to reduced (S) RNA foci and the corresponding RANT products without affecting its (AS) counterparts. ASOs treatment also rescued the cell viability upon stressful stimulus. The results indicate that iNeurons is an advantageous model that not only recapitulates c9ALS/FTD hallmark features but can also help uncover promising therapeutics.
ISSN:1662-453X
1662-4548
1662-453X
DOI:10.3389/fnins.2019.00935