Biology subjects

Quassollo, G.

Publications and source records attributed to Quassollo, G..

4 recordsLinked to original sources

bioRxiv2026

Calcineurin B-mediated Ca2+ sensing translates stress signal intensity into the assembly of phase-separated condensates at PERK complexes.

Endoplasmic reticulum (ER) stress activates protein kinase RNA-like ER kinase (PERK), which initially promotes adaptive responses but remains the only active UPR branch during prolonged stress, mediating both early cytoprotective and chronic pro-apoptotic signaling. Recently, we identified translocon-generated Ca2+ microdomains that promote PERK phosphorylation during early UPR, revealing a mechanism by which local Ca2+ signals regulate UPR activation. However, the molecular mechanism linking these Ca2+ microdomains to PERK activation remains elusive. Previously, we showed that calcineurin (CN), a Ca2+ -dependent heterodimer composed of catalytic (CNA) and regulatory (CNB) subunits, exerts a non-canonical pro-survival function by promoting PERK autophosphorylation. Here, using super-resolution microscopy, CRISPR-Cas9 editing, in silico analyses, and optogenetic droplet assays, we identify CNB as a local Ca2+ sensor that couples translocon-generated Ca2+ signals to liquid condensate assembly, thereby promoting adaptive PERK phosphorylation. These findings establish CNB-mediated condensate assembly as a mechanism that translates local Ca2+ signals into spatially organized early adaptive PERK signaling.

cell biology↗

bioRxiv2025

GM1-oligosaccharide rescues rotenone-impaired neuronal polarization through RhoA/ROCK modulation and mitochondrial protection

Neuronal polarization is a fundamental process in the formation of functional neural circuits, relying on the precise coordination between cytoskeletal regulatory signals and mechanisms that sustain cellular integrity. Disruption of these processes compromises neuronal differentiation and survival, and various neurotoxic compounds, including certain pesticides, have been associated with such dysfunctions. In this context, identifying molecules that counteract these detrimental effects is of significant therapeutic interest. Neuronal polarization is essential for the establishment of functional neural circuits and relies on coordinated regulation of actin cytoskeleton dynamics, RhoA/ROCK signaling, and mitochondrial function. Here, we investigated the neuroprotective and neurorestorative potential of the ganglioside GM1 and its oligosaccharide derivative, osGM1, in primary hippocampal pyramidal neurons exposed to the mitochondrial neurotoxin rotenone. Rotenone induced a marked arrest of neuronal development, impaired axonal elongation, and disrupted mitochondrial organization and membrane potential. Both GM1 and osGM1 promoted recovery of neuronal polarity and axonal growth, exerting protective and restorative effects even under continuous toxin exposure, with osGM1 showing superior efficacy. Notably, osGM1 also reversed axonal growth deficits caused by pathological actin stabilization. Mechanistically, osGM1 normalized rotenone-induced hyperactivation of the RhoA/ROCK pathway without altering basal signaling and partially restored mitochondrial network integrity and function. Collectively, these findings identify osGM1 as a multi-target modulator of cytoskeletal and mitochondrial dysfunction and support its translational potential as a therapeutic strategy to counteract neurotoxin-induced neuronal damage.

neuroscience↗

bioRxiv2023

Dual spatio-temporal regulation of axon growth and microtubule dynamics by RhoA signaling pathways

RhoA plays a crucial role in neuronal polarization, where its action restraining axon outgrowth has been thoroughly studied. We now report that RhoA has not only inhibitory but also a stimulatory effect on axon development depending on when and where exerts its action and the downstream effectors involved. In cultured hippocampal neurons, FRET imaging revealed that RhoA activity selectively localizes in growth cones of undifferentiated neurites, while in developing axons it displays a biphasic pattern, being low in nascent axons and high in elongating ones. RhoA-Rho kinase (ROCK) signaling prevents axon initiation but has no effect on elongation, while formin inhibition reduces axon extension without significantly altering initial outgrowth. Besides, RhoA-mDia promotes axon elongation by stimulating growth cone microtubule stability and assembly, as opposed to RhoA-ROCK that restrains growth cone microtubule assembly and protrusion. Finally, we show that similar mechanisms might operate during axonal regeneration, with RhoA-ROCK slowing axon regrowth after axotomy and RhoA-mDia favoring extension of regenerated axons.

neuroscience↗

bioRxiv2020

Endoplasmic reticulum stress induces a novel Ca2+ signalling system initiated by Ca2+ microdomains

The accumulation of unfolded proteins within the Endoplasmic Reticulum (ER) activates a signal transduction pathway termed the unfolded protein response (UPR), which attempts to restore ER homeostasis. If homeostasis cannot be restored, UPR signalling ultimately induces apoptosis. Ca2+ depletion in the ER is a potent inducer of ER stress. Despite the ubiquity of Ca2+ as intracellular messenger, the precise mechanism (s) by which Ca2+ release affects the UPR remains unknown. Use of a genetically encoded Ca2+ indicator (GCamP6) that is tethered to the ER membrane, uncovered novel Ca2+ signalling events initiated by Ca2+ microdomains in human astrocytes under ER stress, as well as in a cell model deficient in all three IP3 Receptor isoforms. Pharmacological and molecular studies indicate that these local events are mediated by translocons. Together, these data reveal the existence of a previously unrecognized mechanism by which stressor-mediated Ca2+ release regulates ER stress.

cell biology↗