Biology subjects

Di Matteo, F.

Publications and source records attributed to Di Matteo, F..

4 recordsLinked to original sources

bioRxiv2024

Intrinsic and extrinsic mechanisms alter neural cell fate specification in EPM1 Epilepsy

The extracellular milieu, including extracellular vesicles (EVs), plays a pivotal role in brain development by regulating neural processes such as proliferation, differentiation, and migration. In this study, we sought to elucidate the pathogenesis of progressive myoclonus epilepsy type 1 (EPM1), a disease caused by mutations in the CSTB gene, using cerebral organoids (COs) derived from EPM1 patient cells. The results demonstrate that EPM1 COs display increased electrophysiological activity and a disrupted excitatory/inhibitory balance. Single-cell RNA sequencing (scRNA-seq) analysis of ventral EPM1-Cos revealed an abnormal specification of progenitor fate, with a shift toward dorsal neuron identities at the expense of inhibitory interneurons. In addition, pathological alterations in EV biogenesis and cargo were identified, including aberrant Sonic Hedgehog (SHH) signaling, which may disrupt cortical patterning. These findings suggest that both intrinsic progenitor identity shifts and extrinsic EV-mediated signaling contribute to EPM1 pathology. Our study highlights potential therapeutic strategies mediated by EVs as a novel approach to mitigate disease progression.

neuroscience↗

bioRxiv2024

Neuronal Hyperactivity in Neurons Derived from Individuals with Grey Matter Heterotopia

Periventricular heterotopia (PH), a common form of grey matter heterotopia associated with developmental delay and drug-resistant seizures, poses a challenge in understanding its neurophysiological basis. Human cerebral organoids (hCOs) derived from patients with causative mutations in FAT4 or DCHS1 mimic PH features. However, neuronal activity in these 3D models has not yet been invetigated. Here, silicon probe recordings revealed exaggerated spontaneous spike activity in FAT4 and DCHS1 hCOs, suggesting functional changes in neuronal networks. Transcriptome and proteome analyses identified changes in gene ontology terms associated with neuronal morphology and synaptic function. Furthermore, patch-clamp recordings revealed a decreased spike threshold specifically in DCHS1 neurons, likely due to increased somatic voltage-gated sodium channels. Morphological reconstructions and immunostainings revealed greater morphological complexity of PH neurons and synaptic alterations contributing to hyperactivity, with morphological rescue observed in DCHS1 neurons by wild-type DCHS1 expression. Overall, we provide new comprehensive insights into the cellular changes underlying symptoms of grey matter heterotopia.

neuroscience↗

bioRxiv2023

Extracellular vesicle-mediated trafficking of developmental cues is altered during human brain disease

Cellular crosstalk is an essential process influenced by numerous factors including secreted vesicles that transfer nucleic acids, lipids, and proteins between cells. Extracellular vesicles (EVs) have been the center of many studies focusing on neuron-to-neuron communication, but the role of EVs in progenitor-to-neuron and -astrocyte communication and whether EVs display cell-type-specific features for cellular crosstalk during neurogenesis is unknown. Here, using human-derived cerebral organoids, neural progenitors, neurons, and astrocytes, we found that many proteins coded by genes associated with neurodevelopmental disorders are transported via EVs. Thus, we characterized the protein content of EVs and showed their cell type-specific dynamics and function during brain development. Changes in the physiological crosstalk between cells can lead to neurodevelopmental disorders. EVs from patients with epilepsy were found altered in composition and function. Alterations in the intracellular and extracellular compartments highlighted a clear dysregulation of protein trafficking. This study sheds new light on the biology of EVs during brain development and neurodevelopmental disorders. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=185 SRC="FIGDIR/small/546646v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1dad15aorg.highwire.dtl.DTLVardef@e699ccorg.highwire.dtl.DTLVardef@17b371borg.highwire.dtl.DTLVardef@5efa7b_HPS_FORMAT_FIGEXP M_FIG C_FIG Graphical abstract(left) EV uptake mechanism varies depending on the receiving cell type; NPCs transport neuron EVs (nEVs) and astrocyte EVs (aEVs) to the nucleus, astrocytes localize progenitor EVs (pEVs) to the cytoplasm, and neurons retain pEVs and aEVs along the plasma membrane. (right) Cerebral organoids (COs) from progressive Myoclonus Epilepsy Type I (EPM1) patients release EVs lacking key proteins in neurodevelopment and proteins necessary for EV biogenesis and release. Illustration created using BioRender.

developmental biology↗

bioRxiv2021

AMPylation is a specific lysosomal protein posttranslational modification in neuronal maturation.

Protein AMPylation is a pervasive posttranslational modification with an emerging role in neurodevelopment. In metazoans the two highly conserved protein AMP-transferases together with a diverse group of AMPylated proteins have been identified using chemical proteomics and biochemical techniques. However, the function of this modification remains largely unknown. Particularly problematic is the localization of thus far identified AMPylated proteins and putative AMP-transferases. Here, we uncover protein AMPylation as a novel posttranslational modification of luminal lysosomal proteins characteristic in differentiating neurons. Through a combination of chemical proteomics, advanced gel-based separation of modified and unmodified proteins and activity assay, we show that an AMPylated, lysosomal soluble form of exonuclease PLD3 increases dramatically during neuronal maturation and that AMPylation inhibits its catalytic activity. Together, our findings unveil so far unknown lysosomal posttranslational modification, its connection to neuronal differentiation and putatively provide a novel molecular rationale to design of therapeutics for lysosomal storage diseases.

biochemistry↗