Survival and Motor Phenotypes in FVB C9-500 ALS/FTD BAC Transgenic Mice Reproduced by Multiple Labs

Nguyen, Lien; Laboissonniere, Lauren A.; Guo, Shan; Pilotto, Federica; Jacobs, Bart C.; Oestmann, A; Hammond, Jennetta W.; Li, Herman; Hyysalo, Anu; Peltola, Roosa; Pattamatta, Amrutha; Zu, Tao; Voutilainen, Merja H.; Gelbard, Harris A.; Saxena, Smita; Ranum, Laura P.W.

doi:10.1016/j.neuron.2020.09.009

Cited by 31 publications

(28 citation statements)

References 19 publications

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“…The lack of synaptic changes in C9orf72 mice may reflect the fact that no motor phenotypes were observed in any of our C9orf72 mice even by 22 weeks. Our observations are consistent with reports from other groups that the penetrance of the phenotype in this mouse model can be very low in some colonies (Mordes et al, 2020;Nguyen et al, 2020).…”

supporting

confidence: 93%

“…Fig 3A-B). Synaptic maps from 12 week and 22 week old C9orf72 mutant mice of both sexes were obtained to capture reported pre-symptomatic and early-symptomatic stages of the disease phenotype in this model (Liu et al, 2016;Mordes et al, 2020;Nguyen et al, 2020). Mapping PSD95-eGFP synapses revealed no difference in PSD density or size in C9orf72 mice compared to non-Tg controls at either 12 or 22 weeks of age in 150 both males and females (SI.…”

mentioning

confidence: 99%

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Selective Vulnerability of Tripartite Synapses in Amyotrophic Lateral Sclerosis

Broadhead

Bonthron

Waddington

et al. 2021

Preprint

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Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder. Separate lines of evidence suggest that synapses and astrocytes play a role in the pathological mechanisms underlying ALS. Given that astrocytes make specialised contacts with some synapses, called tripartite synapses, we hypothesise that tripartite synapses could act as the fulcrum of disease in ALS. To test this hypothesis, we have performed an extensive microscopy-based investigation of synapses and tripartite synapses in the spinal cord of ALS model mice and post-mortem human tissue from ALS cases. We reveal widescale synaptic changes at the early symptomatic stages of the SOD1G93a mouse model. Super-resolution microscopy reveals that large complex postsynaptic structures are lost in ALS mice. Most surprisingly, tripartite synapses are selectively lost while non-tripartite synapses remain in equal number to healthy controls. Finally, we also observe a similar selective loss of tripartite synapses in human post-mortem ALS spinal cords. From these data we conclude that tripartite synaptopathy is a key hallmark of ALS.

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supporting

confidence: 93%

mentioning

confidence: 99%

Selective Vulnerability of Tripartite Synapses in Amyotrophic Lateral Sclerosis

Broadhead

Bonthron

Waddington

et al. 2021

Preprint

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“…When overexpressing the HRE ( Chew et al, 2015 ; Herranz-Martin et al, 2017 ) or specific DPRs ( Zhang et al, 2016 ; Schludi et al, 2017 ; Choi et al, 2019 ; Hao et al, 2019 ; LaClair et al, 2020 ), both histopathology and some behavioral modifications related to FTD/ALS were observed. However, bacterial artificial chromosome (BAC) transgenic mice mainly reproduced RNA foci formation and DPR inclusions, whereas TDP-43 pathology, neurodegeneration, or FTD/ALS phenotypes were rare or inconstant ( Peters et al, 2015 ; O’Rourke et al, 2016 ; Jiang et al, 2016 ; Liu Y. et al, 2016 ; Mordes et al, 2020 ; Nguyen et al, 2020 ). Spatial learning and anxiety abnormalities accompanied by loss of hippocampal neurons were observed by Jiang et al, but no motor deficits, neuromuscular unit alterations, or differences in social interaction, social recognition, or social communication ( Jiang et al, 2016 ).…”

Section: C9orf72 Haploinsufficiency In Ftd/alsmentioning

confidence: 99%

“…Out of the four groups that generated C9ORF72 BAC mice, only one reported a progressive disease with a motor phenotype leading to hind limb paralysis associated with hippocampal and cortical neuron degeneration, though occurring only in a subset of mice ( Liu Y. et al, 2016 ). Recently, the phenotype of these mice has been debated, as two different research groups did not succeed in reproducing these observations ( Mordes et al, 2020 ) while two others did ( Nguyen et al, 2020 ). An environmental factor was evoked since the experiments were carried out in different laboratories.…”

Section: C9orf72 Haploinsufficiency In Ftd/alsmentioning

confidence: 99%

“…An environmental factor was evoked since the experiments were carried out in different laboratories. Nonetheless, one of the major confounding effects could be the genetic background, as the used FVB/N background is known to present inherent seizure activity ( Nguyen et al, 2020 ). Intriguingly, in the study of Mordes et al, even though DPR inclusions and C9ORF72 RNA foci were present at levels similar to those found in human C9-FTD/ALS brain, the mice did not show any phenotype.…”

Section: C9orf72 Haploinsufficiency In Ftd/alsmentioning

confidence: 99%

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C9ORF72: What It Is, What It Does, and Why It Matters

Smeyers

Banchi

Latouche

2021

Front. Cell. Neurosci.

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When the non-coding repeat expansion in the C9ORF72 gene was discovered to be the most frequent cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in 2011, this gene and its derived protein, C9ORF72, were completely unknown. The mutation appeared to produce both haploinsufficiency and gain-of-function effects in the form of aggregating expanded RNAs and dipeptide repeat proteins (DPRs). An unprecedented effort was then unleashed to decipher the pathogenic mechanisms and the functions of C9ORF72 in order to design therapies. A decade later, while the toxicity of accumulating gain-of-function products has been established and therapeutic strategies are being developed to target it, the contribution of the loss of function starts to appear more clearly. This article reviews the current knowledge about the C9ORF72 protein, how it is affected by the repeat expansion in models and patients, and what could be the contribution of its haploinsufficiency to the disease in light of the most recent findings. We suggest that these elements should be taken into consideration to refine future therapeutic strategies, compensating for the decrease of C9ORF72 or at least preventing a further reduction.

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Selective vulnerability of tripartite synapses in amyotrophic lateral sclerosis

et al. 2022

View full text Add to dashboard Cite

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder. Separate lines of evidence suggest that synapses and astrocytes play a role in the pathological mechanisms underlying ALS. Given that astrocytes make specialised contacts with some synapses, called tripartite synapses, we hypothesise that tripartite synapses could act as the fulcrum of disease in ALS. To test this hypothesis, we have performed an extensive microscopy-based investigation of synapses and tripartite synapses in the spinal cord of ALS model mice and post-mortem human tissue from ALS cases. We reveal widescale synaptic changes at the early symptomatic stages of the SOD1G93a mouse model. Super-resolution microscopy reveals that large complex postsynaptic structures are lost in ALS mice. Most surprisingly, tripartite synapses are selectively lost, while non-tripartite synapses remain in equal number to healthy controls. Finally, we also observe a similar selective loss of tripartite synapses in human post-mortem ALS spinal cords. From these data we conclude that tripartite synaptopathy is a key hallmark of ALS.

show abstract

Survival and Motor Phenotypes in FVB C9-500 ALS/FTD BAC Transgenic Mice Reproduced by Multiple Labs

Cited by 31 publications

References 19 publications

Selective Vulnerability of Tripartite Synapses in Amyotrophic Lateral Sclerosis

Selective Vulnerability of Tripartite Synapses in Amyotrophic Lateral Sclerosis

C9ORF72: What It Is, What It Does, and Why It Matters

Selective vulnerability of tripartite synapses in amyotrophic lateral sclerosis

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