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

Jensen, Brigid K.; Schuldi, Martin H; McAvoy, Kevin; Russell, K.; Boehringer, Ashley; Curran, Bridget Mary; Krishnamurthy, Karthik; Wen, Xinmei; Westergard, Thomas; Ma, Le; Haeusler, Aaron R.; Edbauer, Dieter; Pasinelli, Piera; Trotti, Davide

doi:10.15252/emmm.201910722

Cited by 39 publications

(23 citation statements)

References 73 publications

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“…These ndings provide a novel role of C9orf72 in synaptic physiology at the presynaptic level. Interestingly, consistent with our ndings, SV2a was also recently found at reduce levels in C9orf72-ALS patient-derived IPS neurons 34 . Ablation of SV2a function in knockout models resulted in reduced number of readily releasable pool of synaptic vesicles, diminished release probability and reduction in spontaneous synaptic events 47,48 .…”

Section: Discussionsupporting

confidence: 93%

“…Whether C9orf72 directly or indirectly regulates the level of SV2a in presynaptic compartments remains to be investigated. Intriguingly, similar observations of loss of SV2a and synaptic dysfunction were also observed in neurons expressing the C9orf72-related glycine-alanine (GA) DPR 34 .…”

Section: Discussionmentioning

confidence: 53%

“…Among these proteins, the top hit of dysregulated proteins is the synaptic protein, synaptic vesicle-associated protein 2a (SV2a). Importantly, a recent study showed that SV2a is reduced in C9orf72-ALS patient-derived IPS neurons 34 . This data links the ndings in our C9orf72 loss-of-function model to ALS.…”

Section: C9orf72 Regulates Synaptic Vesicle Exocytosis and Synapse Stmentioning

confidence: 99%

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Reduced C9orf72 function leads to defective synaptic vesicle release and neuromuscular dysfunction in zebrafish

Butti¹,

Giacomotto

Patten³

2020

Preprint

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A hexanucleotide repeat expansion within the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). Reduced levels of C9orf72 mRNA and protein have been found in ALS/FTD patients, but the role of this protein in disease pathogenesis is still poorly understood. Here, we report the generation and characterization of a stable C9orf72 loss-of-function (LOF) model in the zebrafish. We show that reduced C9orf72 function leads to motor defects, muscle atrophy, motor neuron loss and mortality in early larval and adult stages. Analysis of the structure and function of the neuromuscular junctions (NMJs) of the larvae, reveal a significant reduction in the number of presynaptic and postsynaptic structures and an impaired release of quantal synaptic vesicles at the NMJ. Strikingly, we demonstrate a downregulation of SV2a upon C9orf72-LOF and a reduced rate of synaptic vesicle cycling. Furthermore, we show a reduced number and size of Rab3a-postive synaptic puncta at NMJs. Altogether, these results reveal a key function for C9orf72 in the control of presynaptic vesicle trafficking and release at the zebrafish larval NMJ. Our study demonstrates a novel role for C9orf72 in ALS/FTD pathogenesis, where it regulates synaptic vesicle release and neuromuscular functions.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 53%

Section: C9orf72 Regulates Synaptic Vesicle Exocytosis and Synapse Stmentioning

confidence: 99%

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Reduced C9orf72 function leads to defective synaptic vesicle release and neuromuscular dysfunction in zebrafish

Butti¹,

Giacomotto

Patten³

2020

Preprint

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“…They observed that poly (GR) and poly (PR) overexpressing flies presented altered synaptic buttons at NMJs and degeneration of glutamatergic neurons due to excitotoxicity mechanisms. In contrast, Jensen et al (2020) observed that poly(GA) peptides are located in neurites and are less mobile in overexpressing poly(GA) mouse models.…”

Section: C9orf72 Role In Synaptic Dysfunctionmentioning

confidence: 84%

Synaptopathy Mechanisms in ALS Caused by C9orf72 Repeat Expansion

Nishimura

Arias

2021

Front. Cell. Neurosci.

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Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disease caused by degeneration of motor neurons (MNs). ALS pathogenic features include accumulation of misfolded proteins, glutamate excitotoxicity, mitochondrial dysfunction at distal axon terminals, and neuronal cytoskeleton changes. Synergies between loss of C9orf72 functions and gain of function by toxic effects of repeat expansions also contribute to C9orf72-mediated pathogenesis. However, the impact of haploinsufficiency of C9orf72 on neurons and in synaptic functions requires further examination. As the motor neurons degenerate, the disease symptoms will lead to neurotransmission deficiencies in the brain, spinal cord, and neuromuscular junction. Altered neuronal excitability, synaptic morphological changes, and C9orf72 protein and DPR localization at the synapses, suggest a potential involvement of C9orf72 at synapses. In this review article, we provide a conceptual framework for assessing the putative involvement of C9orf72 as a synaptopathy, and we explore the underlying and common disease mechanisms with other neurodegenerative diseases. Finally, we reflect on the major challenges of understanding C9orf72-ALS as a synaptopathy focusing on integrating mitochondrial and neuronal cytoskeleton degeneration as biomarkers and potential targets to treat ALS neurodegeneration.

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“…Besides protein sequestration and proteasomal inhibition, poly-GA expression was found to decrease the efficiency of DNA double-strand break repair mechanisms, specifically impacting non-homologous end joining, single-strand annealing, and microhomology-mediated end joining processes ( Andrade et al, 2020 ). Furthermore, mobile poly-GA aggregates can be found in the axons and dendrites of primary cortical and motor neurons overexpressing the poly-GA DPR ( Jensen et al, 2020 ). Evidence indicates that neurons with poly-GA aggregates have increased Ca 2+ influx in response to an external stimulus; nevertheless, the synaptic release is abrogated in these neurons.…”

Section: Non-arginine Dprsmentioning

confidence: 99%

Emerging Perspectives on Dipeptide Repeat Proteins in C9ORF72 ALS/FTD

Schmitz

Marques

Oertig

et al. 2021

Front. Cell. Neurosci.

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The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide expansion in the chromosome 9 open reading frame 72 gene (C9ORF72). This hexanucleotide expansion consists of GGGGCC (G4C2) repeats that have been implicated to lead to three main modes of disease pathology: loss of function of the C9ORF72 protein, the generation of RNA foci, and the production of dipeptide repeat proteins (DPRs) through repeat-associated non-AUG (RAN) translation. Five different DPRs are currently known to be formed: glycine–alanine (GA) and glycine–arginine (GR) from the sense strand, proline–alanine (PA), and proline–arginine (PR) from the antisense strand, and glycine–proline (GP) from both strands. The exact contribution of each DPR to disease pathology is currently under intense scrutiny and is still poorly understood. However, recent advances in both neuropathological and cellular studies have provided us with clues enabling us to better understand the effect of individual DPRs on disease pathogenesis. In this review, we compile the current knowledge of specific DPR involvement on disease development and highlight recent advances, such as the impact of arginine-rich DPRs on nucleolar protein quality control, the correlation of poly-GR with neurodegeneration, and the possible involvement of chimeric DPR species. Further, we discuss recent findings regarding the mechanisms of RAN translation, its modulators, and other promising therapeutic options.

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

Cited by 39 publications

References 73 publications

Reduced C9orf72 function leads to defective synaptic vesicle release and neuromuscular dysfunction in zebrafish

Reduced C9orf72 function leads to defective synaptic vesicle release and neuromuscular dysfunction in zebrafish

Synaptopathy Mechanisms in ALS Caused by C9orf72 Repeat Expansion

Emerging Perspectives on Dipeptide Repeat Proteins in C9ORF72 ALS/FTD

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