Mutant C9orf72 human iPSC-derived astrocytes cause non-cell autonomous motor neuron pathophysiology.
Chen Zhao,Anna-Claire Devlin,Anna-Claire Devlin,Amit K. Chouhan,Amit K. Chouhan,Bhuvaneish T. Selvaraj,Maria Stavrou,Karen Burr,Veronica Brivio,Veronica Brivio,Xin He,Arpan R Mehta,David Story,Christopher Shaw,Owen Dando,Giles E. Hardingham,Gareth B. Miles,Gareth B. Miles,Siddharthan Chandran +18 more
TLDR
It is shown that mutant astrocytes both recapitulate key aspects of C9orf72‐related ALS pathology and, upon co‐culture, cause motor neurons to undergo a progressive loss of action potential output due to decreases in the magnitude of voltage‐activated Na+ and K+ currents.Abstract:
Mutations in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS). Accumulating evidence implicates astrocytes as important non-cell autonomous contributors to ALS pathogenesis, although the potential deleterious effects of astrocytes on the function of motor neurons remains to be determined in a completely humanized model of C9orf72-mediated ALS. Here, we use a human iPSC-based model to study the cell autonomous and non-autonomous consequences of mutant C9orf72 expression by astrocytes. We show that mutant astrocytes both recapitulate key aspects of C9orf72-related ALS pathology and, upon co-culture, cause motor neurons to undergo a progressive loss of action potential output due to decreases in the magnitude of voltage-activated Na+ and K+ currents. Importantly, CRISPR/Cas-9 mediated excision of the C9orf72 repeat expansion reverses these phenotypes, confirming that the C9orf72 mutation is responsible for both cell-autonomous astrocyte pathology and non-cell autonomous motor neuron pathophysiology.read more
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C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD (P4.001)
Robert H. Baloh,Jacqueline G. O’Rourke,Shaughn Bell,Laurent Bogdonik,A. K. M. G. Muhammad,Tania F. Gendron,Kevin J. Kim,Andrew Austin,Janet Cady,Elaine Liu,Jonah Zarrow,Sharday Grant,Ritchie Ho,Sharon Carmona,Megan Simpkinson,Kathryn Wu,Lillian M. Daughrity,Dennis W. Dickson,Matthew B. Harms,Leonard Petrucelli,Cathleen M. Lutz +20 more
TL;DR: Transgenic mice carrying a bacterial artificial chromosome containing the full human C9orf72 gene with either a normal allele (15 repeats) or disease-associated expansion (∼100-1,000 repeats; C9-BACexp) are reported, supporting the hypothesis that RNA foci and RAN dipeptides occur presymptomatically and are not sufficient to drive neurodegeneration in mice at levels seen in patients.
Journal ArticleDOI
Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis
Arpan R Mehta,Jenna M. Gregory,Owen Dando,Roderick N. Carter,Karen Burr,Jyoti Nanda,David Story,Karina McDade,Colin Smith,Nicholas M. Morton,Don J. Mahad,Giles E. Hardingham,Siddharthan Chandran,Bhuvaneish T. Selvaraj +13 more
TL;DR: In this paper, the authors showed that loss of mitochondrial function is a key mediator of axonal dysfunction in C9orf72-ALS, and that boosting motor neuron bioenergetics is sufficient to restore axonal homeostasis.
Journal ArticleDOI
Non-neuronal cells in amyotrophic lateral sclerosis - from pathogenesis to biomarkers.
Björn Friedhelm Vahsen,Elizabeth Gray,Alexander G. Thompson,Olaf Ansorge,Daniel C. Anthony,Sally A. Cowley,Kevin Talbot,Martin R Turner +7 more
TL;DR: In this article, the authors provide an overview of the diverse roles of non-neuronal cells in relation to the pathogenesis of amyotrophic lateral sclerosis (ALS) and the emerging potential of nonneuron cell biomarkers to advance therapeutic development.
Journal ArticleDOI
Glial Cells-The Strategic Targets in Amyotrophic Lateral Sclerosis Treatment.
TL;DR: Current knowledge regarding the involvement of each glial cell type in the progression of ALS, currently available treatments, and to provide an overview of diverse clinical trials covering pharmacological approaches, gene, and cell therapies are summarized.
Journal ArticleDOI
C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility
Laura Fumagalli,Florence L. Young,Steven Boeynaems,Mathias De Decker,Arpan R. Mehta,Ann Swijsen,Raheem Fazal,Wenting Guo,Matthieu Moisse,Jimmy Beckers,Lieselot Dedeene,Bhuvaneish T. Selvaraj,Tijs Vandoorne,Vanesa Madan,Marka van Blitterswijk,Denitza Raitcheva,Alexander McCampbell,Koen Poesen,Aaron D. Gitler,Philipp Koch,Philipp Koch,Pieter Vanden Berghe,Dietmar Rudolf Thal,Catherine M. Verfaillie,Siddharthan Chandran,Ludo Van Den Bosch,Simon L. Bullock,Philip Van Damme +27 more
TL;DR: In this article, a hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
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