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

• Published in: Frontiers in neuroscience Vol. 13; p. 935
• Main Authors: Bauer, Peter O., Dunmore, Judith H., Sasaguri, Hiroki, Matoska, Vaclav
• Format: Journal Article
• Language: English
• Published: Lausanne Frontiers Research Foundation 06-09-2019; Frontiers Media S.A
• 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; Czech Republic
• ISSN: 1662-453X; 1662-4548; 1662-453X
• DOI: 10.3389/fnins.2019.00935

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.