Biology subjects

Caraveo, G.

Publications and source records attributed to Caraveo, G..

5 recordsLinked to original sources

bioRxiv2025

BASP1 Couples Ca2+ Signaling and Actin Polymerization to Mitochondrial Fission Essential for Neurite Outgrowth

Actin-mediated mitochondrial fission is essential for cellular homeostasis, yet the mechanisms by which actin is recruited to mitochondria and how it couples the outer and inner mitochondrial membranes (IMM) remain poorly understood. Using a phosphoproteomic screen in a rat model of -synucleinopathy, we identified BASP1 as a calcineurin-dependent substrate that is constitutively dephosphorylated under pathological Ca2+ elevations and phosphorylated under neuroprotective calcineurin inhibition. Immunoprecipitation and mass spectrometry of phosphomutant BASP1 expressed in neurons revealed that dephosphorylation promotes interactions with actin and IMM proteins. Dephosphorylated BASP1 recruits actin to mitochondria, while subsequent phosphorylation enables actin-mediated mitochondrial fission and neurite elongation. Constitutive dephosphorylation, as it occurs in -synucleinopathy, impairs mitochondrial fission, inhibits neurite growth and promotes -synuclein aggregation. Our findings position BASP1 as a Ca2+-CaN-regulated hub that coordinates actin remodeling and couples mitochondrial membranes to drive fission, revealing a mechanistic axis linking mitochondrial dysfunction to neuronal morphogenesis and -synuclein pathobiology.

cell biology↗

bioRxiv2025

SNARE Protein Ykt6 Drives AMPAR Insertion at Synaptic Terminals During LTP

Long-Term Potentiation (LTP), a crucial form of synaptic plasticity essential for memory and learning, depends on protein synthesis and the upregulation of GluA1 at postsynaptic terminals. While extensive research has focused on the role of endosomal trafficking in GluA1 regulation, the contribution of endoplasmic reticulum (ER) trafficking pathways remains largely unexplored. A key opportunity to investigate this emerged from Ykt6, an evolutionarily conserved SNARE protein and a master regulator of vesicular fusion along ER-trafficking pathways. Here, we demonstrate that Ykt6 is highly expressed in the mammalian hippocampus, where it localizes to synaptic spines and regulates GluA1 surface expression in an LTP-dependent manner. Furthermore, we found that Ykt6 modulates synaptic vesicle pool dynamics as well as the amplitude and frequency of miniature excitatory postsynaptic currents. Ykt6 loss of function has been linked to -synuclein pathology, a hallmark of Lewy Body Dementias (LBDs), where -synuclein misfolding in the hippocampus disrupts LTP. Taken together, our findings establish Ykt6 as a critical SNARE protein in hippocampal function during LTP, with significant implications for neurodegenerative disorders such as LBDs.

neuroscience↗

bioRxiv2025

Calcineurin-mediated regulation of GAP-43 is essential for neurite and synapse formation and protects against α-synuclein-induced degeneration

IntroductionElevated calcium (Ca2+) levels and hyperactivation of the Ca2+-dependent phosphatase calcineurin are key factors in -synuclein (-syn) pathobiology in Dementia with Lewy Bodies and Parkinsons Disease (PD). Calcineurin activity can be inhibited by FK506, an FDA-approved compound. Our previous work demonstrated that sub-saturating doses of FK506 provide neuroprotection against -syn pathology in a rat model of -syn neurodegeneration, an effect associated with the phosphorylation of growth-associated protein 43 (GAP-43). MethodsTo investigate the role of GAP-43 phosphorylation, we generated phosphomutants at the calcineurin-sensitive sites and expressed them in PC12 cells and primary rat cortical neuronal cultures to assess their effects on neurite morphology and synapse formation. Additionally, we performed immunoprecipitation mass spectrometry in HeLa cells to identify binding partners of these phosphorylation sites. Finally, we evaluated the ability of these phosphomutants to modulate -syn toxicity. ResultsIn this study, we demonstrate that calcineurin-regulated phosphorylation at S86 and T172 of GAP-43 is a crucial determinant of neurite branching and synapse formation. A phosphomimetic GAP-43 mutant at these sites enhances both processes and provides protection against -syn-induced neurodegeneration. Conversely, the phosphoablative mutant prevents neurite branching and synapse formation while exhibiting increased interactions with ribosomal proteins. DiscussionOur findings reveal a novel mechanism by which GAP-43 activity is regulated through phosphorylation at calcineurin-sensitive sites. These findings suggest that FK506s neuroprotective effects may be partially mediated through GAP-43 phosphorylation, providing a potential target for therapeutic intervention in synucleinopathies.

neuroscience↗

bioRxiv2022

Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein

Octopamine is a well-established invertebrate neurotransmitter involved in fight-or-flight responses. In mammals, its function was replaced by norepinephrine. Nevertheless, it is present at trace amounts and can modulate the release of monoamine neurotransmitters by a yet unidentified mechanism. Here, through a multidisciplinary approach utilizing in vitro and in vivo models of -synucleinopathy, we uncovered an unprecedented role for octopamine in driving the conversion from toxic to neuroprotective astrocytes in the cerebral cortex by fostering aerobic glycolysis. Physiological levels of neuron-derived octopamine act on astrocytes via a TAAR1-Orai1-Ca2+-calcineurin-mediated signaling pathway to stimulate lactate secretion. Lactate uptake in neurons via the MCT2-calcineurin-dependent pathway increases ATP and prevents neurodegeneration. Pathological increases of octopamine caused by -synuclein halts lactate production in astrocytes and short-circuits the metabolic communication to neurons. Our work provides a novel function of octopamine as a modulator of astrocyte metabolism and subsequent neuroprotection with implications to -synucleinopathies.

neuroscience↗

bioRxiv2020

A conformational switch driven by phosphorylation regulates Ykt6 activity in macroautophagy

Membrane fusion, an essential process in all eukaryotes, is driven by SNARE proteins. Ykt6 is an essential SNARE that plays critical roles throughout the secretory, endocytic, and autophagy pathways. Ykt6 activity is thought to be regulated by a conformational change from a closed cytosolic form to an open membrane-bound form, yet the mechanism that regulates this transition is unknown. Through genetic, pharmacologic, and structural modeling approaches in mammalian cells, we found that phosphorylation regulates Ykt6 conversion from a closed to an open state. The phosphorylation site we identified is highly conserved in evolution and is regulated by the Ca2+-dependent phosphatase, calcineurin. We found that phosphorylation is a key determinant for intracellular localization of Ykt6 and its function in macroautophagy. Our studies reveal a novel mechanism by which Ykt6 conformation and activity is regulated by Ca2+ signaling with implications in Parkinsons Disease in which Ykt6 has been shown to play a role.

cell biology↗