Biology subjects

Carrettiero, D. C.

Publications and source records attributed to Carrettiero, D. C..

5 recordsLinked to original sources

bioRxiv2026

Disrupted Brain Organoid Circuitry, Structural Organization, and Spine Morphology in 7q11.23 Copy Number Variant Syndromes

The 7q11.23 chromosomal region represents a model of gene dosage-dependence, where a hemizygous deletion causes Williams Syndrome (WS) and a duplication leads to 7q11.23 Duplication Syndrome (Dup7). It is not understood how these copy number variations (CNVs) disrupt development and functional cortical circuit assembly. Utilizing iPSC-derived cerebral organoids and longitudinal imaging from post-differentiation day 30 to 150, we characterized the aberrant neural rosette morphogenesis in WS and Dup7 during early stages, establishing an early structural divergence from control lines. We observed accelerated early cortical rosette morphogenesis in WS, characterized by a premature increase in both rosette number and layer thickness compared to controls. In contrast, Dup7 organoids consistently exhibit a significantly lower number and reduced thickness of rosettes from early stages onward. This early structural disruption progressively impacted synaptic-level architecture as the organoids matured. Dendritic spine characterization at later stages revealed Dup7 organoids exhibited a significantly higher dendritic spine density compared to WS. Pharmacological antagonism of CCR5 (C-C chemokine receptor type 5) with Maraviroc significantly enhanced dendritic spine density in control and WS organoids; however, this effect was absent in Dup7. To determine how these structural anomalies translate into circuit-level behavior, we performed longitudinal calcium imaging using GCaMP. Control organoids sustained synchronized activity and high spike correlations at all time points. This synchronization was delayed and highly transient in WS organoids, and completely abolished in Dup7 organoids, which exhibit significantly low spike correlations at all stages. Developmentally, GABA changes from acting as an excitatory signal in the immature brain to an inhibitory signal as the brain matures. As control lines matured gabazine-induced desynchronization progressively diminished, but persisted in WS organoids. Dup7 organoids failed to establish synchronization at any developmental time point, but displayed a negligible increased synchrony following gabazine treatment. These functional aberrations were paralleled by genotype-specific defects in structural organization, specifically in rosette morphogenesis and dendritic spine density. Collectively, our findings demonstrate that 7q11.23 CNVs trigger pathogenic neurodevelopmental defects by derailing the trajectories of structural organization, circuit assembly, and functional synchronization during cortical maturation.

neuroscience↗

bioRxiv2026

BAG2 Condensates Couple Proteostasis to CD8+T Cell Surveillance

Protein aggregation, impaired degradation, and immune activation are central hallmarks of neurodegenerative diseases, yet how these processes are coordinated remains unclear. Here, we identify Immune-Protein Degradation Bodies (I-PDBs), a previously unrecognized class of BAG2-driven, phase-separated organelles that integrate protein quality control with adaptive immunity. IFN{gamma} induce I-PDB formation at the endoplasmic reticulum (ER), where they concentrate immunoproteasome components, MHC-I peptide-loading machinery, and ER-associated chaperones. I-PDBs redirect proteostatic cargo from centrosomal aggregation pathways to spatially restricted degradation sites optimized for antigenic peptide generation, coupling selective substrate clearance to CD8 T cell engagement. Using a cellular model of aggregation-prone tau, we show that I-PDBs capture pathological tau fibrils at ER-microtubule interfaces and process them into potentially antigenic peptides, thus reducing the load of aggregation-prone tau peptides. We term this mechanism the Proteostasis-Associated Immune Relay (PAIR), establishing I-PDBs as critical hubs linking proteostasis to immune surveillance with broad implications for disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/719751v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@16fa503org.highwire.dtl.DTLVardef@ba7607org.highwire.dtl.DTLVardef@19ae5bdorg.highwire.dtl.DTLVardef@60fdf7_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIIFN{gamma} drives BAG2-dependent Immune-Protein Degradation Bodies (I-PDBs) C_LIO_LII-PDBs assemble at the endoplasmic reticulum and are enriched in immunoproteasome and MHC-I machinery C_LIO_LII-PDBs shunt misfolded proteins, including pathological tau, away from aggresomes C_LIO_LII-PDBs couple proteostasis to antigen presentation, enhancing CD8 T cell recognition C_LIO_LIThe Proteostasis-Associated Immune Relay (PAIR) defines a pathway linking proteostasis to adaptive immunity C_LI

cell biology↗

bioRxiv2025

Progranulin loss induces mitochondrial dysfunction and ferroptosis in human cerebral organoids

Loss-of-function mutations in the granulin (GRN) gene cause frontotemporal dementia when the mutations are heterozygous and neuronal ceroid lipofuscinosis, a lysosomal storage disease, when homozygous. While it is well established that disease-causing GRN mutations decrease progranulin (PGRN) levels, leading to neurodegeneration, the cellular and molecular mechanisms underlying these conditions remain poorly understood. In this study, we utilized human induced pluripotent stem cell (iPSC) derived forebrain organoids to investigate the impact of PGRN homozygous deficiency on neuronal and glial cell populations. Through single-cell RNA sequencing, we identified robust downregulation of the mitochondrial oxidative phosphorylation pathway in PGRN KO organoids. In line with these results, PGRN KO organoids showed decreased mitochondrial respiration. Furthermore, our study demonstrated that PGRN loss induced increased levels of reactive oxygen species (ROS), lipid peroxidation and iron accumulation. Finally, we observed increased vulnerability to ferroptotic cell death in PGRN KO organoids. Our findings suggest that mitochondrial dysfunction and impaired responses to oxidative stress are early manifestations of PGRN loss, and offer insights into the molecular mechanisms driving neurodegeneration caused by PGRN deficiency. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/691344v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@c477e5org.highwire.dtl.DTLVardef@9b61eforg.highwire.dtl.DTLVardef@13aadeborg.highwire.dtl.DTLVardef@1702929_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO Proposed molecular mechanisms that lead to ferroptosis of PGRN KO cells. Created with BioRender.com. C_FIG

neuroscience↗

bioRxiv2021

Methylmalonic acid impairs cell respiration and glutamate uptake in C6 rat glioma cells

Methylmalonic acidemia is an organic acidemia caused by deficient activity of L-methylmalonyl-CoA mutase or its cofactor cyanocobalamin and it is biochemically characterized by an accumulation of methylmalonic acid (MMA) in tissue and body fluids of patients. The main clinical manifestations of this disease are neurological and observable symptoms during metabolic decompensation are encephalopathy, cerebral atrophy, coma, and seizures, which commonly appear in newborns. This study aimed to investigate the toxic effects of MMA in a glial cell line presenting astrocytic features. Astroglial C6 cells were exposed to MMA (0.1-10mM) for 24 or 48 hours and cell viability, glucose consumption and oxygen consumption rate, as well as glutamate uptake and ATP content were analyzed. The possible preventive effects of bezafibrate were also evaluated. MMA significantly reduced cell viability after 48-hour period and increased glucose consumption during the same period of incubation. Regarding the energy homeostasis, MMA significantly reduced respiratory parameters of cells after 48-hour exposition, indicating that cell metabolism is compromised at resting and reserve capacity state, which might influence the cell capacity to meet energetic demands. Glutamate uptake and ATP content were also compromised after exposition to MMA, which can be influenced energy metabolism impairment, affecting the functionality of the astroglial cells. Our findings suggest that these effects could be involved in the pathophysiology of neurological dysfunction of this disease.

neuroscience↗

bioRxiv2020

Methylmalonic acid compromises mitochondrial respiration and reduces the expression of markers of differentiation in SH-SY5Y human neuroblastoma cells

Methylmalonic acidemia is a rare metabolic disorder characterized by the accumulation of methylmalonic acid (MMA) and alternatives metabolites which is caused by the deficient activity of L-methylmalonyl-CoA mutase or its cofactor 5-deoxyadenosylcobalamin (AdoCbl). The brain is one of the affected tissues by the accumulation of this metabolite in patients. The neurologic symptoms commonly appear in newborns and are clinically characterized by seizures, mental retardation, psychomotor abnormalities, and coma. The molecular mechanisms of neuropathogenesis in methylmalonic acidemia are still poorly understood, specifically regarding the impairments in neuronal development and maturation. In this study, we firstly investigated the neurotoxicity of MMA in both undifferentiated and 7-day RA-differentiated phenotypes of SH-SY5Y human neuroblastoma cells and found alterations in energetic homeostasis after the exposition to MMA. We observed an increase in glucose consumption and reduced respiratory parameters of both undifferentiated and differentiated SH-SY5Y cells after 48 hours of exposition to MMA. RA-differentiated cells slightly indicated to be more prone to perturbations in respiratory parameters by MMA than undifferentiated cells. In order to understand whether the presence of MMA during neuronal maturation could compromise this process in neuronal cells, we performed high-resolution respirometry to evaluate the mitochondria function and qPCR assay to evaluate mRNA levels of mature neuronal-specific genes in early-stage (day 3), and late-stage (day 7) of differentiation in cells co-treated with MMA 1mM during RA mediated differentiation. Our results showed that MMA compromises the respiratory parameters of routine, ATP-linked, and maximal respiration only at the late stage of differentiation as well as downregulates the transcriptional gene profile of mature neuronal markers ENO2 and SYP. Altogether, our finds point to important alterations observed during neuronal maturation and energetic stress vulnerability that can play a role in the neurological clinical symptoms at the newborn period and reveal important molecular mechanisms that could help the screening of targets to new approaches in the therapies of this disease.

biochemistry↗