Dataset Information

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

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.

SUBMITTER: Bauer PO

PROVIDER: S-EPMC6743368 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Bauer Peter O PO Dunmore Judith H JH Sasaguri Hiroki H Matoska Vaclav V

Frontiers in neuroscience 20190906

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative conditions. A non-coding hexanucleotide (GGGGCC) repeat expansion in the <i>c9orf72</i> 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 ...[more]

PMID: 31551693

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Project description:Purpose of reviewPeripheral nervous system vasculitides (PNSV) are a heterogeneous group of disorders with a clinical subset that may differ in prognosis and therapy. We provide a comprehensive update on the clinical assessment, diagnosis, complications, treatment, and follow-up of PNSV.Recent findingsProgress in neuroimaging, molecular testing, and peripheral nerve biopsy has improved clinical assessment and decision-making of PNSV, also providing novel insights on how to prevent misdiagnosis and increase diagnostic certainty. Advances in imaging techniques, allowing to clearly display the vessel walls, have also enhanced the possibility to differentiate inflammatory from non-inflammatory vascular lesions, while recent histopathology data have identified the main morphological criteria for more accurate diagnosis and differential diagnoses. Overall, the identification of peculiar morphological findings tends to improve diagnostic accuracy by defining a clearer boundary between systemic and non-systemic neuropathies. Therefore, the definition of epineurium vessel wall damage, type of vascular lesion, characterization of lymphocyte populations, antibodies, and inflammatory factors, as well as the identification of direct nerve damage or degeneration, are the common goals for pathologists and clinicians, who will both benefit for data integration and findings translation. Nevertheless, to date, treatment is still largely empiric and, in some cases, unsatisfactory, thus often precluding precise prognostic prediction. In this context, new diagnostic techniques and multidisciplinary management will be essential in the proper diagnosis and prompt management of PNSV, as highlighted in the present review. Thirty to fifty percent of all patients with vasculitis have signs of polyneuropathy. Neuropathies associated with systemic vasculitis are best managed according to the guidelines of the underlying disease because appropriate workup and initiation of treatment can reduce morbidity. Steroids, or in severe or progressive cases, cyclophosphamide pulse therapy is the standard therapy in non-systemic vasculitic neuropathies. Some patients need long-term immunosuppression. The use of novel technologies for high-throughput genotyping will permit to determine the genetic influence of related phenotypes in patients with PNSV.

Dataset Information

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

Publications

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

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