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

Butti, Zoé; Pan, Yingzhou Edward; Giacomotto, Jean; Patten, Shunmoogum A.

doi:10.1038/s42003-021-02302-y

Cited by 51 publications

(39 citation statements)

References 61 publications

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“…In agreement with our data revealing a role for C9orf72 in the regulation of synaptic vesicle pools, downregulation of SV2 and a reduced rate of synaptic vesicle cycling has been observed at the neuromuscular junction in a zebrafish C9orf72 loss of function model [10]. Reductions in SV2 and the size of readily releasable pool of vesicles were also reported in C9orf72-ALS patient-derived induced pluripotent stem cell (iPSC) cortical neurons [36,57], but, while we observed reduced SV2 in hippocampal neurons in vitro after C9orf72 knockdown, and a C9orf72 gene dosage-dependent decrease in vivo in the hippocampus of C9orf72-HET and C9orf72-KO mice (Figs.…”

Section: Discussionsupporting

confidence: 93%

An interaction between synapsin and C9orf72 regulates excitatory synapses and is impaired in ALS/FTD

et al. 2022

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Dysfunction and degeneration of synapses is a common feature of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). A GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene is the main genetic cause of ALS/FTD (C9ALS/FTD). The repeat expansion leads to reduced expression of the C9orf72 protein. How C9orf72 haploinsufficiency contributes to disease has not been resolved. Here we identify the synapsin family of synaptic vesicle proteins, the most abundant group of synaptic phosphoproteins, as novel interactors of C9orf72 at synapses and show that C9orf72 plays a cell-autonomous role in the regulation of excitatory synapses. We mapped the interaction of C9orf72 and synapsin to the N-terminal longin domain of C9orf72 and the conserved C domain of synapsin, and show interaction of the endogenous proteins in synapses. Functionally, C9orf72 deficiency reduced the number of excitatory synapses and decreased synapsin levels at remaining synapses in vitro in hippocampal neuron cultures and in vivo in the hippocampal mossy fibre system of C9orf72 knockout mice. Consistent with synaptic dysfunction, electrophysiological recordings identified impaired excitatory neurotransmission and network function in hippocampal neuron cultures with reduced C9orf72 expression, which correlated with a severe depletion of synaptic vesicles from excitatory synapses in the hippocampus of C9orf72 knockout mice. Finally, neuropathological analysis of post-mortem sections of C9ALS/FTD patient hippocampus with C9orf72 haploinsufficiency revealed a marked reduction in synapsin, indicating that disruption of the interaction between C9orf72 and synapsin may contribute to ALS/FTD pathobiology. Thus, our data show that C9orf72 plays a cell-autonomous role in the regulation of neurotransmission at excitatory synapses by interaction with synapsin and modulation of synaptic vesicle pools, and identify a novel role for C9orf72 haploinsufficiency in synaptic dysfunction in C9ALS/FTD.

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Section: Discussionsupporting

confidence: 93%

An interaction between synapsin and C9orf72 regulates excitatory synapses and is impaired in ALS/FTD

et al. 2022

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“…These deficits were rescued by expressing the human WT C9orf72 mRNA, highlighting the specificity of the induced phenotype [300]. These data have been also confirmed by other groups [301,302], thus supporting that C9orf72 LoF mechanisms may underlie defects of the synaptic function at NMJ in ALS. On the other side, expression of longer repeats provokes C9orf72 GoF, which resulted in RNA foci initiating cell apoptosis [303], reduced motor axonal growth and aberrant branching [304].…”

Section: Zebrafish Carrying C9orf72 Mutationssupporting

confidence: 73%

Nearly 30 Years of Animal Models to Study Amyotrophic Lateral Sclerosis: A Historical Overview and Future Perspectives

Bonifacino

Zerbo

Balbi

et al. 2021

IJMS

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Amyotrophic lateral sclerosis (ALS) is a fatal, multigenic, multifactorial, and non-cell autonomous neurodegenerative disease characterized by upper and lower motor neuron loss. Several genetic mutations lead to ALS development and many emerging gene mutations have been discovered in recent years. Over the decades since 1990, several animal models have been generated to study ALS pathology including both vertebrates and invertebrates such as yeast, worms, flies, zebrafish, mice, rats, guinea pigs, dogs, and non-human primates. Although these models show different peculiarities, they are all useful and complementary to dissect the pathological mechanisms at the basis of motor neuron degeneration and ALS progression, thus contributing to the development of new promising therapeutics. In this review, we describe the up to date and available ALS genetic animal models, classified by the different genetic mutations and divided per species, pointing out their features in modeling, the onset and progression of the pathology, as well as their specific pathological hallmarks. Moreover, we highlight similarities, differences, advantages, and limitations, aimed at helping the researcher to select the most appropriate experimental animal model, when designing a preclinical ALS study.

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“…However, L5-PYRs from asymptomatic C9orf72 carriers demonstrated a significant decrease in the mIPSC frequency, albeit with a preserved density of inhibitory inputs, pointing to a reduced probability of GABA release as a potential mechanism. Recently, a down-regulation of the synaptic vesicle protein SV2a upon c9orf72 loss of function has been associated with a reduced rate of synaptic vesicle cycling at the zebrafish larval neuromuscular junction (Butti et al, 2021). Interestingly, in mammalian neurons, the SV2a exhibits a high expression specifically at inhibitory synapses, where it plays an important role in sorting of synaptotagmin I (Bae et al, 2020), thus offering a plausible mechanism that can be responsible for early deficit in GABA release in M1 L5-PYRs of c9-500 mice.…”

Section: Discussionmentioning

confidence: 99%

Enhanced motor cortex output and disinhibition in asymptomatic female mice with C9orf72 genetic expansion

Amalyan¹,

Tamboli²,

Lazarevich³

et al. 2022

Cell Reports

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

Cited by 51 publications

References 61 publications

An interaction between synapsin and C9orf72 regulates excitatory synapses and is impaired in ALS/FTD

An interaction between synapsin and C9orf72 regulates excitatory synapses and is impaired in ALS/FTD

Nearly 30 Years of Animal Models to Study Amyotrophic Lateral Sclerosis: A Historical Overview and Future Perspectives

Enhanced motor cortex output and disinhibition in asymptomatic female mice with C9orf72 genetic expansion

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