C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity

Selvaraj, Bhuvaneish T.; Livesey, Matthew R.; Zhao, Chen; Gregory, Jenna M; James, Owain T.; Cleary, Elaine M.; Chouhan, Amit K.; Gane, Angus B; Perkins, Emma M.; Dando, Owen; Lillico, Simon; Lee, Youn-bok; Nishimura, Agnes L.; Poreci, Urjana; Thankamony, Sai; Pray, Meryll; Vasistha, Navneet A.; Magnani, Dario; Borooah, Shyamanga; Burr, Karen; Story, David; McCampbell, Alexander; Shaw, Christopher E.; Kind, Peter C.; Aitman, Timothy J.; Whitelaw, Bruce; Wilmut, Ian; Smith, Colin; Miles, Gareth B.; Hardingham, Giles E.; Wyllie, David J. A.; Chandran, Siddharthan

doi:10.1038/s41467-017-02729-0

Cited by 172 publications

(238 citation statements)

References 73 publications

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“…Derived from RNAscope® assays, BaseScope® in situ hybridization techniques enables the detection of degraded oligonucleotides in postmortem, formalin fixed paraffin embedded tissues, when antigen detection is impaired and no longer possible (Selvaraj et al, ; https://acdbio.com/science/applications/research-areas/post-mortem-brain-tissue). The present approach developed in nonhuman primates therefore helps to bridge the gap between murine description of the RTN and its identification in humans, using similar specific markers.…”

Section: Discussionmentioning

confidence: 99%

“…RTN neurons overlapped with Phox2b-ir neurons in the ventral respiratory group. (a) dorsal view, (b) from upper-right side, (c) caudal view, (d) rostral view [Color figure can be viewed at wileyonlinelibrary.com] postmortem, formalin fixed paraffin embedded tissues, when antigen detection is impaired and no longer possible (Selvaraj et al, 2018; https://acdbio.com/science/applications/research-areas/postmortem-brain-tissue). The present approach developed in nonhuman primates therefore helps to bridge the gap between murine description of the RTN and its identification in humans, using similar specific markers.…”

Section: Discussionmentioning

confidence: 99%

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Tridimensional mapping of Phox2b expressing neurons in the brainstem of adult Macaca fascicularis and identification of the retrotrapezoid nucleus

Lévy

Facchinetti

Jan

et al. 2019

J of Comparative Neurology

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Chemosensitivity is a key mechanism for the regulation of breathing in vertebrates. The retrotrapezoid nucleus is a crucial hub for respiratory chemoreception within the brainstem. It integrates chemosensory information that are both peripheral from the carotid bodies (via the nucleus of the solitary tract) and central through the direct sensing of extracellular protons. To date, the location of a genetically defined RTN has only been ascertained in rodents. We first demonstrated that Phox2b, a key determinant for the development of the visceral nervous system and branchiomotor nuclei in the brainstem including the RTN, had a similar distribution in the brainstem of adult macaques compared to adult rats. Second, based on previous description of a specific molecular signature for the RTN in rats, and on an innovative technique for duplex in situ hybridization, we identified parafacial neurons which coexpressed Phox2b and ppGal mRNAs. They were located ventrally to the nucleus of the facial nerve and extended from the caudal part of the nucleus of the superior olive to the rostral tip of the inferior olive. Using the previously described blockface technique, deformations were corrected to allow the proper alignment and stacking of digitized sections, hence providing for the first time a 3D reconstruction of the macaque brainstem, Phox2b distribution and the primate retrotrapezoid nucleus. This description should help bridging the gap between rodents and humans for the description of key respiratory structures in the brainstem.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tridimensional mapping of Phox2b expressing neurons in the brainstem of adult Macaca fascicularis and identification of the retrotrapezoid nucleus

Lévy

Facchinetti

Jan

et al. 2019

J of Comparative Neurology

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“…Eight iPSC lines were used in this study, including two healthy controls (Con‐1 and Con‐2), three ALS patient lines carrying the G 4 C 2 repeat expansion in the C9orf72 gene (C9‐1, C9‐2 and C9‐3) and 3 isogenic control lines C9‐1 (C9‐Δ1), C9‐2 (C9‐Δ2), and C9‐3 (C9‐Δ3). IPSCs were generated from fibroblasts using either Sendai virus or retrovirus expressing the Yamanaka transcription factors (OCT3/4, SOX2, c‐Myc, and KLF4) (Bilican et al, ; Devlin et al, ; Selvaraj et al, ; Takahashi et al, ). These were conducted under full Ethical/Institutional Review Board approval at the University of Edinburgh (Con‐1 and Con‐2), at University College London (C9‐1) and at King's College of London (C9‐2 and C9‐3).…”

Section: Methodsmentioning

confidence: 99%

“…IPSCs were generated from fibroblasts using either Sendai virus or retrovirus expressing the Yamanaka transcription factors (OCT3/4, SOX2, c-Myc, and KLF4) (Bilican et al, 2012;Devlin et al, 2015;Selvaraj et al, 2018;Takahashi et al, 2007). These were conducted under full Ethical/Institutional Review Board approval at the University of Edinburgh (Con-1 and Con-2), at University College London (C9-1) and at King's College of London (C9-2 and C9-3).…”

Section: Generation Of Ipsc Lines and Isogenic Control Ipsc Linesmentioning

confidence: 99%

“…An important advance in human iPSC‐based disease modeling is the use of paired isogenic control lines which help establish causality between a given mutation and phenotypes (Sandoe & Eggan, ; Selvaraj, Livesey, & Chandran, ; Wang et al, ). Using CRISPR/Cas9‐mediated genome editing to selectively excise G 4 C 2 repeats we have recently shown selective human MN vulnerability to AMPA receptor mediated excitotoxicity that is mutation dependent (Selvaraj et al, ). In this study, we have utilized this system to further explore the cell‐autonomous and non‐cell autonomous consequences of C9orf72 mutation on iPSC‐derived astrocytes and MNs.…”

Section: Introductionmentioning

confidence: 99%

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Mutant C9orf72 human iPSC‐derived astrocytes cause non‐cell autonomous motor neuron pathophysiology

Zhao

Devlin

Chouhan

et al. 2019

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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.

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Parafacial neurons in the human brainstem express specific markers for neurons of the retrotrapezoid nucleus

Lévy

Droz-Bartholet

Achour

et al. 2021

J of Comparative Neurology

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The retrotrapezoid nucleus (RTN) is a hub for respiratory chemoregulation in the mammal brainstem that integrates chemosensory information from peripheral sites and central relays. Chemosensitive neurons of the RTN express specific genetic and molecular determinants, which have been used to identify RTN precise location within the brainstem of rodents and nonhuman primates. Based on a comparative approach, we hypothesized that among mammals, neurons exhibiting the same specific molecular and genetic signature would have the same function. The co‐expression of preprogalanin (PPGAL) and SLC17A6 (VGluT2) mRNAs with duplex in situ hybridization has been studied in formalin fixed paraffin‐embedded postmortem human brainstems. Two specimens were processed and analyzed in line with RTN descriptions in adult rats and macaques. Double‐labeled PPGAL+/SLC17A6+ neurons were only identified in the parafacial region of the brainstem. These neurons were found surrounding the nucleus of the facial nerve, located ventrally to the nucleus VII on caudal sections, and slightly more dorsally on rostral sections. The expression of neuromedin B (NMB) mRNA as a single marker of chemosensitive RTN neurons has not been confirmed in humans. The location of the RTN in human adults is provided. This should help to develop investigation tools combining anatomic high‐resolution imaging and respiratory functional investigations to explore the pathogenic role of the RTN in congenital or acquired neurodegenerative diseases.

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C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity

Cited by 172 publications

References 73 publications

Tridimensional mapping of Phox2b expressing neurons in the brainstem of adult Macaca fascicularis and identification of the retrotrapezoid nucleus

Tridimensional mapping of Phox2b expressing neurons in the brainstem of adult Macaca fascicularis and identification of the retrotrapezoid nucleus

Mutant C9orf72 human iPSC‐derived astrocytes cause non‐cell autonomous motor neuron pathophysiology

Parafacial neurons in the human brainstem express specific markers for neurons of the retrotrapezoid nucleus

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