Biology subjects

Falcone, C.

Publications and source records attributed to Falcone, C..

4 recordsLinked to original sources

bioRxiv2025

Varicose-projection astrocytes: a reactive phenotype associated with neuropathology

Glial cells are fundamental for the pathophysiology of all neurological disorders. Astrocytes, the primary home-ostatic cells of the central nervous system (CNS), exhibit species-specific characteristics, with human astrocytes specifically displaying unique structural and functional features. It is thus essential to investigate human-specific astrocytic responses to neuropathology using human-relevant models. Varicose projection (VP) astrocytes, traditionally considered specific to humans and apes, were suggested to reflect pathological burden, albeit direct evidence linking them to neurological diseases has been lacking. Here, we demonstrate for the first time that VP astrocytes are present in mice and tigers (Panthera tigris) and we provide evidence from four distinct human-based models that VP astrocytes are not a distinct physiological astrocyte subtype but rather a novel class of reactive astrocytes associated with neuropathology. Using human induced pluripotent stem cell (hiPSC)-derived astrocytes, mixed neural cultures, and cortical organoids, we showed that VP astrocytes are induced by pro-inflammatory cytokines interleukin-1{beta} (IL-1{beta}) and tumor necrosis factor- (TNF-) or LPS. Notably, cytokine withdrawal reverses the VP phenotype of astrocytes, indicating that it is a transient, inflammation-dependent state. We characterized the distinctive components of varicosities, including markers for extracellular vesicles, mitochondria, Golgi and endoplasmic reticulum components, suggesting roles in cellular stress responses and metabolic dysregulation. We further validated the pathological relevance of VP astrocytes by documenting their significant enrichment in postmortem brain samples from patients with several neurodegenerative diseases including as Alzheimers disease, Parkinsons disease, and multiple sclerosis, as well as in surgical resections from patients with epilepsy due to hippocampal sclerosis or brain tumors, including previously unreported subcortical regions such as basal ganglia. Additionally, we identified a higher number of VP astrocytes also in mouse astrocytes upon treatment with pro-inflammatory cytokines, suggesting that formation of VP astrocytes is an evolutionarily conserved astrocytic response to neuroinflammation. Our findings point to VP astrocytes as a novel reactive astrocyte subtype closely linked to neuropathology, highlighting their potential as biomarkers and therapeutic targets in neurological diseases. This study lays the groundwork for future investigations into the mechanisms driving VP astrocyte formation and their broader implications in neuropathology.

neuroscience↗

bioRxiv2024

A focal traumatic injury to the spinal cord causes an immediate and massive spreading depolarization sustained by chloride ions, with transient network dysfunction and remote cortical glia changes.

In clinics, physical injuries to the spinal cord cause a temporary motor areflexia below lesion, known as spinal shock. This topic is still underexplored due to the lack of preclinical SCI models that do not use anesthesia, which would affect spinal excitability. Our innovative design considered a custom-made micro impactor that provides localized and calibrated strikes to the ventral surface of the thoracic spinal cord of the entire CNS isolated from neonatal rats. Before and after injury, multiple ventral root (VR) recordings continuously traced respiratory rhythm, baseline spontaneous activities, and electrically-induced reflex responses. As early as 200 ms after impact, an immediate transient depolarization spread from the injury site to the whole spinal cord with distinct segmental velocities. Stronger strikes induced higher potentials causing, at the site of injury, a transient drop in tissue oxygen levels and a massive cell death with complete disconnection of longitudinal tracts. Below the impact site, expiratory rhythm and spontaneous lumbar activity were suppressed. On lumbar VRs, reflex responses transiently halted but later recovered to control values, while electrically-induced fictive locomotion remained perturbed. Moreover, low-ion modified Krebs solutions differently influenced impact-induced depolarizations, the magnitude of which amplified in low-Cl-. Moreover, remote changes in cortical glia occurred soon after spinal damage. Overall, our novel in vitro platform traces the immediate functional consequences of impacts to the spinal cord during development. This basic study provides insights on the SCI pathophysiology, unveiling an immediate chloride dysregulation and transient remote glial changes in the cortex.

neuroscience↗

bioRxiv2022

Transcription, structure, and organoids translate time across the lifespan of humans and great apes

How the neural structures supporting human cognition develop and arose in evolution is an enduring question of interest. Yet, we still lack appropriate procedures to align ages across primates, and this lacuna has hindered progress in understanding the evolution of biological programs. We generated a dataset of unprecedented size consisting of 573 time points from abrupt and gradual changes in behavior, anatomy, and transcription across human and 8 non-human primate species. We included time points from diverse human populations to capture within-species variation in the generation of cross-species age alignments. We also extracted corresponding ages from organoids. The identification of corresponding ages across the lifespan of 8 primate species, including apes (e.g., orangutans, gorillas) and monkeys (i.e., marmosets, macaques) reveal that some biological pathways are extended in humans compared with some non-human primates. Particularly, the human lifespan is unusually extended relative to studied nonhuman primates demonstrating that very old age is a phase of life in humans that does not map to other studied primate species. More generally, our work prompts a reevaluation in the choice of a model system to understand aging given very old age in humans is a period of life with a clear counterpart in great apes. Significance StatementWhat is special about the duration of human development and aging has been an enduring source of interest. A significant hurdle in identifying which biological programs are unusually extended in humans is the lack of standardized approaches with which to align ages across species. We harnessed temporal variation in behavior, transcription, and anatomy to align ages across the lifespan of primates. These data reveal which biological programs are conserved, and which are modified. Harnessing time points across scales of study guides the choice of model systems to understand disease progression, and can be used to enhance care of great apes, many of which are critically endangered.

neuroscience↗

bioRxiv2021

Oligodendrocytes are a lifelong source of nuclear and ribosomal material for neurons in the mouse brain

Nuclear and ribosomal components define cell identity and function by regulating chromatin dynamics, gene expression, and protein turnover. Here we report that in the mouse central nervous system (CNS) under normal conditions, neurons accumulate nuclear and ribosomal material of oligodendrocyte (OL) origin. We show that neuronal accumulation of OL-derived nuclear and ribosomal material is brain area-specific, and in the cortex and hippocampal dentate gyrus gradually propagates during postnatal brain maturation. We further demonstrate that OL-to-neuron material transfer persists throughout adulthood and responds to neuroinflammation. We found that satellite OL of the gray matter form internuclear contacts with receiving neurons in the mouse brain. Similar close internuclear associations between satellite OL and neurons are present in the adult human cortex. Our findings provide the first evidence of wide-spread dynamic and selective OL-to-neuron nuclear and ribosomal material transfer in the mouse CNS and indicate that satellite OL serve as powerful mediators of neuronal function. Equivalent processes may occur in the human CNS and cause neurological disorders when dysregulated. One Sentence SummaryNeurons receive OL-derived nuclear and ribosomal material

neuroscience↗