Biology subjects

Pellier, E.

Publications and source records attributed to Pellier, E..

3 recordsLinked to original sources

bioRxiv2025

Lipid transfer by ORP3 is required for the regulation of PI4P and PI(4,5)P2 at the plasma membrane in mitosis

During mitosis, cellular contents including the genetic material and membrane-bound organelles must be faithfully distributed between the two daughter cells. Regulation of PI(4,5)P2 levels at the plasma membrane is essential for mitotic progression, including anchoring of the mitotic spindle, recruitment of the actomyosin cytoskeleton at the cleavage furrow, and abscission. Here, we demonstrate that the ORP3 lipid transfer protein, which transfers PI4P from the plasma membrane to the endoplasmic reticulum (ER) at ER-plasma membrane contacts, plays a crucial role in the regulation of PI4P and PI(4,5)P2 levels at the plasma membrane in mitosis. We show that defects in ORP3 function alter PI4P and PI(4,5)P2 distributions, distribution of the actin cytoskeleton at the plasma membrane, mitotic spindle geometry, chromosome segregation, abscission, and lead to the accumulation of multinucleated cells. The function of ORP3 in mitosis is dependent on its ER-partner VAPA and phosphorylation of the ORP3 VAPA-binding motif strongly recruits ORP3 to the ER, priming it for PI4P transfer from the plasma membrane to the ER. Finally ORP3 is required to prevent PI4P accumulation at the cytoplasmic bridge as a result of PI(4,5)P2 hydrolysis for abscission and successful completion of cell division. Altogether, ORP3 plays a key role in PI4P and PI(4,5)P2 regulation during mitosis. Impairment of ORP3 function results in multiple cell division phenotypes, leading to genetic instability and aneuploidy.

cell biology↗

bioRxiv2025

DAB2 as a biomarker and mechanistic link between lipid dysregulation and disease progression in LGMD R2

Limb-girdle muscular dystrophy R2 (LGMD R2) is an autosomal recessive disorder caused by dysferlin deficiency, leading to progressive muscle weakness and wasting. Despite advances in understanding the mechanisms linking dysferlin loss to membrane fragility and muscle degeneration, the lack of robust clinical biomarkers has limited disease monitoring and therapeutic evaluation. Here, we identify Disabled-2 (DAB2) as a molecular and clinical biomarker for LGMD R2. Transcriptomic profiling revealed a significant upregulation of DAB2 in induced pluripotent stem cell (iPSC)-derived myotubes from patients with LGMD R2. Its expression correlated with disease severity in muscle biopsies from a cohort of 14 dysferlin-deficient individuals and in dysferlin knockout Bla/J mice, where levels increased with disease progression. Crucially, we demonstrate that DAB2 upregulation in muscle is normalized following treatment with AAV gene therapy expressing full-length dysferlin, positioning DAB2 as a dynamic biomarker for both disease monitoring and therapeutic response. Based on the role of DAB2 in lipid trafficking and the reported pathological lipid accumulation in LGMD R2, we then investigated its contribution to disease-associated lipid dysregulation. Consistent with this hypothesis, we show that high DAB2 levels paralleled lipid deposition in affected patients, iPSC-derived myotubes and mouse muscles, while siRNA- mediated DAB2 knockdown reduced lipid accumulation in LGMD R2 myotubes. Together, our findings establish DAB2 as a mechanistic link between disease severity and lipid dysregulation, and highlight its potential as a key prognostic marker, opening new avenues for precision medicine approaches in LGMD R2 and other related muscular dystrophies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/675589v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@152c1f1org.highwire.dtl.DTLVardef@3af57eorg.highwire.dtl.DTLVardef@cb4630org.highwire.dtl.DTLVardef@16d384b_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2022

Dual blockade of misfolded alpha-sarcoglycan degradation by bortezomib and givinostat combination

Limb-girdle muscular dystrophy type R3 (LGMD R3) is a rare genetic disorder characterized by a progressive proximal muscle weakness and caused by mutations in the SGCA gene encoding alpha-sarcoglycan (-SG). Here, we report the results of a mechanistic screening ascertaining the molecular mechanisms involved in the degradation of the most prevalent misfolded R77C--SG protein. We performed a combinatorial study to identify drugs potentializing the effect of a low dose of the proteasome inhibitor bortezomib on the R77C--SG degradation inhibition. Analysis of the screening associated to artificial intelligence-based predictive ADMET characterization of the hits led to identification of the HDAC inhibitor givinostat as potential therapeutical candidate. Functional characterization revealed that givinostat effect was related to autophagic pathway inhibition, unveiling new theories concerning degradation pathways of misfolded SG proteins. Beyond the identification of a new therapeutic option for LGMD R3 patients, our results shed light on the potential repurposing of givinostat for the treatment of other genetic diseases sharing similar protein degradation defects such as LGMD R5 and cystic fibrosis.

pharmacology and toxicology↗