Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS (original) (raw)

“…Moreover, further differentiation of iPSC-derived neural progenitors into astrocytes can take further 6-8 weeks, with neuronal contamination remaining an issue for a considerable period of the process, though eventually faltering at 2% or less (53,54). The breakthrough in the field of cell reprogramming in ALS research came with the development of a novel protocol for fibroblast reprogramming, which utilises the same defined factors as iPSC technology and manages to bypass the iPSC stage by converting fibroblast directly into induced neural progenitor cells (iNPCs) (17). The protocol lasts approximately 3-4 weeks, thus significantly shortening the reprogramming process.…”

Section: Human Astrocytesmentioning

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“…Moreover, further differentiation of iPSC-derived neural progenitors into astrocytes can take further 6-8 weeks, with neuronal contamination remaining an issue for a considerable period of the process, though eventually faltering at 2% or less (53,54). The breakthrough in the field of cell reprogramming in ALS research came with the development of a novel protocol for fibroblast reprogramming, which utilises the same defined factors as iPSC technology and manages to bypass the iPSC stage by converting fibroblast directly into induced neural progenitor cells (iNPCs) (17). The protocol lasts approximately 3-4 weeks, thus significantly shortening the reprogramming process.…”

Section: Human Astrocytesmentioning

“…The protocol lasts approximately 3-4 weeks, thus significantly shortening the reprogramming process. Moreover, a highly enriched astrocyte culture (~95%) can be obtained after a week of further differentiation without a need for selection steps or purification (17). Skin biopsy samples used in this study have been obtained from sporadic patients and those carrying either a SOD1 mutation or expressing a C9orf72 repeat expansion.…”

Section: Human Astrocytesmentioning

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“…Genetic instability, dysfunction of the promoter region, abnormal mRNA distribution, splicing and translation are also linked to the formation of G-quadruplexes (or G-tetrads) of uni and multimolecular RNA 24 . Besides this intraneuronal mechanisms, it has been demonstrated that ALS patients carrying C9orf72 mutations have astrocytes that convey toxicity towards motor neurons 30 . The so-called GGGGCC (G4C2) n hexanucleotide repeat expansion, in the normal asymptomatic individual, ranges from 2 to 19 repeats, despite the fact of up to 30 repeats being also considered normal.…”

Section: Genetic Aspects and Pathophysiologymentioning