Biology subjects

Zaouter, C.

Publications and source records attributed to Zaouter, C..

3 recordsLinked to original sources

bioRxiv2025

Therapeutic modulation of the calpastatin/calpain pathway restores calpain-mediated synaptic proteolysis and preserves motor neurons survival and function in C9orf72 ALS

A hexanucleotide repeat expansion (GGGGCC) in the C9orf72 gene is the most prevalent genetic cause of ALS, with early neuromuscular junction (NMJ) dysfunction being a key pathological feature. Current therapies provide only limited symptomatic relief, underscoring the need for targeted, mechanism-based interventions. Using a C9orf72 ALS zebrafish model (C9-miR) and patient-derived induced pluripotent stem cell (iPSC) motor neurons, we identified significant downregulation of calpastatin, the endogenous inhibitor of calpains, a calcium-dependent protease family implicated in neurodegeneration. We demonstrate that restoring calpastatin activity with a cell-permeable calpastatin-derived peptide or the small molecule, calpeptin, ameliorates locomotor deficits and NMJ dysfunction in the C9-miR zebrafish model. These interventions enhance synaptic vesicle turnover and quantal release at the NMJ while improving motor neuron excitability and synaptic integrity in iPSC-derived motor neurons. N-terminomic/TAILS mass spectrometry revealed direct calpain-mediated cleavage of synaptic proteins in motor neurons derived from C9orf72 patients. Proteolysis of novel ALS-relevant synaptic and axonal proteins is prevented by calpeptin and calpastatin peptide treatments. Our findings establish the calpastatin as a pivotal regulator of synaptic function in C9orf72-associated ALS and identify it as a promising therapeutic target, offering a novel strategy to restore synaptic transmission and potentially halt disease progression.

neuroscience↗

bioRxiv2024

RFC1 regulates the expansion of neural progenitors in the developing zebrafish cerebellum

DNA replication and repair are basic yet essential molecular processes for all cells. RFC1 encodes the largest subunit of the Replication Factor C (RFC), which is a clamp-loader during DNA replication and repair. Intronic repeat expansion in RFC1 has recently been associated with so-called RFC1-related disorders, which mainly encompass late-onset cerebellar ataxias. However, the mechanisms that make certain tissues more susceptible to defects in these universal pathways remain mysterious. In this study, we provide the first investigation of RFC1 gene function in vivo using zebrafish. We showed that RFC1 is expressed in neural progenitor cells within the developing cerebellum and that it is necessary to maintain these cells genomic integrity during neurogenic maturation. Accordingly, RFC1 loss-of-function leads to a severe cerebellar phenotype due to impaired neurogenesis of both Purkinje and granule cells. Our data thus point to a specific role of RFC1 in the developing cerebellum, paving the way for a better understanding of the pathogenic mechanisms underlying RFC1-related disorders.

developmental biology↗

bioRxiv2018

Restriction of chromatin accessibility is necessary for appropriate enhancer expression

Tissue specific gene expression underpins cell type diversity, and arises from the cooperative activities of transcription factors and the chromatin landscape. It has been previously demonstrated that enhancers with specific arrangements of transcription factor binding motifs can bring together commonly and specifically expressed factors in order to stabilize chromatin accessibility and drive spatially restricted reporter expression within different regions of the CNS. However, when reporters were used to analyse the activity of enhancers bound differentially by a common factor in the endoderm and CNS, several examples of non-tissue specific reporter expression were observed. In order to judge whether or not this may have been due to the unregulated chromatin environment of exogenously delivered enhancer reporters, here we have analysed the chromatin landscape of cells from the CNS and endodermal tissues and find that this reflects neighbouring gene expression to a greater degree than transcription factor binding. This work demonstrates that chromatin accessibility plays an essential role in defining enhancer activity in distantly related cell types.

developmental biology↗