Defects in synaptic transmission at the neuromuscular junction precede motor deficits in a TDP‐43
            <sup>Q331K</sup>
            transgenic mouse model of amyotrophic lateral sclerosis

Chand, Kirat K.; Lee, Kah Meng; Lee, John D.; Qiu, Hao; Willis, Emily F.; Lavidis, Nickolas A.; Hilliard, Massimo A.; Noakes, Peter G.

doi:10.1096/fj.201700835r

Cited by 47 publications

(43 citation statements)

References 72 publications

(114 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Loss of functional communication between presynaptic motor neurons and postsynaptic muscle is the hallmark feature of all forms of ALS and has been advocated as a promising target for therapeutic intervention. In a recent report using a mouse model expressing the ALS‐causative TDP‐43 Q331K mutation, neurotransmission deficits in the form of defects in synaptic vesicle fusion and release, decreased probability of release, and reduced quantal content of vesicles were described 7 months prior to motor neuron loss (Chand et al , ). The disease causative GGGGCC hexanucleotide repeat expansion in C9orf72 is no exception to this principle; in fact, early synaptic deficits have now been identified in paradigms modeling this mutation and have been suggested as potential targetable disease features (Sareen et al , ; Devlin et al , ).…”

Section: Discussionmentioning

confidence: 99%

Synaptic dysfunction induced by glycine‐alanine dipeptides in C9orf72‐ ALS / FTD is rescued by SV 2 replenishment

et al. 2020

View full text Add to dashboard Cite

The most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an intronic hexanucleotide repeat expansion in the C9orf72 gene. In disease, RNA transcripts containing this expanded region undergo repeat-associated non-AUG translation to produce dipeptide repeat proteins (DPRs), which are detected in brain and spinal cord of patients and are neurotoxic both in vitro and in vivo paradigms. We reveal here a novel pathogenic mechanism for the most abundantly detected DPR in ALS/FTD autopsy tissues, poly-glycine-alanine (GA). Previously, we showed motor dysfunction in a GA mouse model without loss of motor neurons. Here, we demonstrate that mobile GA aggregates are present within neurites, evoke a reduction in synaptic vesicle-associated protein 2 (SV2), and alter Ca 2+ influx and synaptic vesicle release. These phenotypes could be corrected by restoring SV2 levels. In GA mice, loss of SV2 was observed without reduction of motor neuron number. Notably, reduction in SV2 was seen in cortical and motor neurons derived from patient induced pluripotent stem cell lines, suggesting synaptic alterations also occur in patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Synaptic dysfunction induced by glycine‐alanine dipeptides in C9orf72‐ ALS / FTD is rescued by SV 2 replenishment

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons. The early dysfunction and loss of neuromuscular junctions (NMJs) is a key event in patients and animal models of the disease (Fischer et al, 2004;Pun et al, 2006;Armstrong and Drapeau, 2013a,b;Clark et al, 2016;Tallon et al, 2016;Tremblay et al, 2017;Chand et al, 2018). A recent study has shown in SOD1 G37R mice that NMJ loss within single motor-units (MUs), defined as a motor neuron and the muscle fibers it innervates, is initially slow and asynchronous (Martineau et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

Martineau

Polo

Velde

et al. 2020

eNeuro

View full text Add to dashboard Cite

Progressive loss of neuromuscular junctions (NMJs) is an early event in amyotrophic lateral sclerosis (ALS), preceding the global degeneration of motor axons and being accompanied by new axonal sprouting within the same axonal arbor. Some aspects of ALS onset and progression seem to be affected by sex in animal models of the disease. However, whether there are sex-specific differences in the pattern or time course of NMJ loss and repair within single motor axons remains unknown. We performed further analysis of a previously published in vivo dataset, obtained from male and female SOD1 G37R mice. We found that NMJ losses are as frequent in male and female motor axons but, intriguingly, axonal sprouting is more frequent in female than male mice, resulting in a net increase of axonal arborization. Interestingly, these numerous new axonal branches in female mice are associated with a slightly faster decline in grip strength, increased NMJ denervation, and reduced a-motor neuron survival. Collectively, these results suggest that excessive axonal sprouting and motorunit (MU) expansion in female SOD1 G37R mice are maladaptive during ALS progression.Sex-specific differences in amyotrophic lateral sclerosis (ALS) progression have been identified in patients and in some animal models of the disease. However, the physio-pathologic changes underlying these disparities remain poorly defined. In this study, we identified that the pattern of motor axon retraction and regrowth in skeletal muscles is a novel factor to consider in our understanding of sex-linked differences in ALS. Analysis of single motor axons in a model of ALS identified that female motor axons were more likely to form compensatory branches, which was associated with a worse phenotype. These surprising findings highlight the necessity to more systematically evaluate the prevalence of sex-specific differences across animal models of ALS and in patients.

show abstract

“…The prion protein promoter ensures that the transgene expression is directed primarily to the central nervous system - the brain and spinal cord - and is very low in other peripheral tissue [15]. Female WT and TDP-43 Q331K mice at 16 months based on their motor deficits were used in this study [16,17]. Compound TDP-43 WTxQ331K mice were generated by breeding TDP-43 WT and TDP-43 Q331K mice as described previously [18].…”

Section: Methodsmentioning

confidence: 99%

Absence of receptor for advanced glycation end product (RAGE) reduces inflammation and extends survival in the hSOD1^G93A mouse model of amyotrophic lateral sclerosis

Lee

McDonald

Fung

et al. 2020

Preprint

View full text Add to dashboard Cite

1Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron 2 degenerative disease that is without effective treatment. The receptor for advanced glycation 3 end products (RAGE) is a major component of the innate immune system that has been 4 implicated in ALS pathogenesis. However, the contribution of RAGE signaling to the 5 neuroinflammation that underlies ALS neurodegeneration remains unknown. The present study 6 therefore generated SOD1 G93A mice lacking RAGE, and compared them to SOD1 G93A 7 transgenic ALS mice in respect to disease progression (i.e. body weight, survival and muscle 8 strength), neuroinflammation and denervation markers in the spinal cord and tibialis anterior 9 muscle. We found that complete absence of RAGE signaling exerted a protective effect on 10 SOD1 G93A pathology, slowing disease progression and significantly extending survival by ~3 11 weeks, and improving motor function (rotarod and grip strength). This was associated with 12 reduced microgliosis, cytokines, innate immune factors (complement, TLRs, inflammasomes), 13 and oxidative stress in the spinal cord, and a reduction of denervation markers in the tibialis 14 anterior muscle. We also documented that RAGE mRNA expression was significantly 15 increased in the spinal cord and muscles of preclinical SOD1 and TDP43 models of ALS, 16 supporting a widespread involvement for RAGE in ALS pathology. In summary, our results 17 indicate that RAGE signalling drives neuroinflammation and contributes to neurodegeneration 18 in ALS, and highlights RAGE as a potential immune therapeutic target for ALS. 19 20 21 22 23 24

show abstract

Defects in synaptic transmission at the neuromuscular junction precede motor deficits in a TDP‐43 ^Q331K transgenic mouse model of amyotrophic lateral sclerosis

Cited by 47 publications

References 72 publications

Synaptic dysfunction induced by glycine‐alanine dipeptides in C9orf72‐ ALS / FTD is rescued by SV 2 replenishment

Synaptic dysfunction induced by glycine‐alanine dipeptides in C9orf72‐ ALS / FTD is rescued by SV 2 replenishment

Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

Absence of receptor for advanced glycation end product (RAGE) reduces inflammation and extends survival in the hSOD1^G93A mouse model of amyotrophic lateral sclerosis

Contact Info

Product

Resources

About

Defects in synaptic transmission at the neuromuscular junction precede motor deficits in a TDP‐43 Q331K transgenic mouse model of amyotrophic lateral sclerosis

Cited by 47 publications

References 72 publications

Synaptic dysfunction induced by glycine‐alanine dipeptides in C9orf72‐ ALS / FTD is rescued by SV 2 replenishment

Synaptic dysfunction induced by glycine‐alanine dipeptides in C9orf72‐ ALS / FTD is rescued by SV 2 replenishment

Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

Absence of receptor for advanced glycation end product (RAGE) reduces inflammation and extends survival in the hSOD1G93A mouse model of amyotrophic lateral sclerosis

Contact Info

Product

Resources

About

Defects in synaptic transmission at the neuromuscular junction precede motor deficits in a TDP‐43 ^Q331K transgenic mouse model of amyotrophic lateral sclerosis

Absence of receptor for advanced glycation end product (RAGE) reduces inflammation and extends survival in the hSOD1^G93A mouse model of amyotrophic lateral sclerosis