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

Peter O Bauer,Vaclav Matoska,Judith H Dunmore,Hiroki Sasaguri

doi:10.3389/fnins.2019.00935

Peter O Bauer, Vaclav Matoska + Show 2 more

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https://doi.org/10.3389/fnins.2019.00935

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Abstract

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 of ALS/FTD. We present a cellular model of c9ALS/FTD where induced neurons (iNeurons) are generated within 2 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 decreased (S) RNA foci staining and a reduction of 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.

Highlights

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases with significant genetic, neuropathological, and clinical overlap (Lillo and Hodges, 2009; Walsh and Hochedlinger, 2010)
Punch skin biopsies were performed on the anterior aspect of the forearm from six individuals visiting Department of Neurology of Mayo Clinic, which included three control participants and three repeat expansion carriers
In an attempt to develop human neuronal disease models with endogenous mutation, we extended this finding to adult human dermal fibroblasts (HDFs)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases with significant genetic, neuropathological, and clinical overlap (Lillo and Hodges, 2009; Walsh and Hochedlinger, 2010). ALS is characterized by selective degeneration of upper and lower motor neurons causing muscle weakness, spasticity, atrophy, and death within 1–5 years after disease onset (Cleveland and Rothstein, 2001; Bruijn et al, 2004). FTD is one of the most common early onset dementias (Ratnavalli et al, 2002) characterized by neuronal degeneration in the frontal and temporal lobes causing a progressive deterioration of behavior, language, and personality (Bozeat et al, 2000). An expanded non-coding hexanucleotide repeat expansion [r(GGGGCC)exp] in the chromosome 9 open reading frame 72 (c9orf72) gene has been identified as the most common genetic cause underlying FTD and ALS (c9ALS/FTD) (DeJesus-Hernandez et al, 2011; Renton et al, 2011).

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