Biology subjects

Matsas, R.

Publications and source records attributed to Matsas, R..

5 recordsLinked to original sources

bioRxiv2025

Mitochondrial membrane junction-mediated ATP channeling drives activity-dependent glucose metabolism

Neurons and brown adipocytes rely on rapid ATP production from accelerated glucose metabolism to sustain bursts of activity upon stimulation, a process known as activity-dependent glucose metabolism. The first committed step in this pathway, the hexokinase I (HK1)-catalyzed phosphorylation of glucose, consumes ATP, raising the question of how this reaction can be accelerated when cytosolic ATP becomes limiting during stimulation. We identify Cell Cycle Exit and Neuronal Differentiation protein 1 (CEND1), expressed in both cell types, as a critical regulator of this process. Loss of CEND1 impairs activity-dependent glucose utilization, ATP generation, and stimulation-evoked activity both in vitro and in vivo. Mechanistically, CEND1 assembles a complex with HK1, voltage-dependent anion channel 1 (VDAC1), and adenine nucleotide translocase 1 (ANT1) at hemifusion-like membrane junction between the outer/inner mitochondrial membrane, channeling mitochondrially derived ATP directly to HK1. These findings uncover a previously unrecognized mechanism that sustains activity-dependent glucose metabolism, with broad implications for energy homeostasis in specialized cell types.

physiology↗

bioRxiv2024

Proteostasis dysregulation in p.A53T-α-Synuclein iPSC-derived astrocytes exacerbates neurodegeneration in a Parkinson's disease model with Lewy-like pathology

Alpha-Synuclein (Syn) plays a central role in Parkinsons disease (PD) and the p.A53T mutation causes an early-onset familial form of PD with severe manifestations. The pathological effects of the p.A53T-Syn mutation have been extensively investigated in neurons, yet the consequences on astrocytes and astrocytic contribution to PD pathology are understudied. Here, we differentiated induced pluripotent stem cells from PD patients carrying the p.A53T-Syn mutation to astrocytes, which uncovered cell-intrinsic phenotypes, including calcium dyshomeostasis and accumulation of protein aggregates. Proteomic profiling and functional analyses revealed perturbed protein catabolic processes, involving the proteasome and autophagy, associated with lysosomal malfunction. Dopamine neurons co-cultured with p.A53T-Syn astrocytes displayed exacerbated neurodegeneration with hallmark Lewy-like pathologies, reversed by control astrocytes at least due to their ability to resolve neuronal Syn aggregates by endocytic clearance. Our findings underscore a critical impact of p.A53T-Syn on astrocytic protein quality control mechanisms, positioning astrocytes as important contributors to PD neuropathology. HighlightsO_LIiPSC-derived astrocytes from PD patients with the p.A53T-Syn mutation display cell-autonomous pathological phenotypes and toxic Syn accumulation C_LIO_LIProteome and functional analyses reveal failure of major proteostasis mechanisms in p.A53T-Syn astrocytes, largely related to lysosomal malfunction C_LIO_LIInherent Lewy-like pathological features are identified in p.A53T-Syn astrocyte-neuron co-cultures C_LIO_LIp.A53T-Syn astrocytes induce PD-relevant neuropathology to healthy neurons C_LIO_LIControl but not p.A53T-Syn astrocytes alleviate neuropathology in co-cultured neurons C_LI

neuroscience↗

bioRxiv2023

Age-induced midbrain-striatum assembloids model early phenotypes of Parkinsons disease

Parkinsons disease (PD), one of the most common aging-associated neurodegenerative disorders, is characterised by nigrostriatal pathway dysfunction, caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the midbrain and the dopamine depletion in the striatum. State of the art, human in vitro models are enabling the study of the dopaminergic neurons loss, but not the dysregulation of the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics which potentially contribute to the development of PD. Therefore, it is conceivable that research conducted using these models overlooked numerous processes that contribute to diseases phenotypes. Here we present a nigrostriatal pathway model based on midbrain-striatum assembloids with inducible aging. We show that these assembloids are capable of developing characteristics of the nigrostriatal connectivity, with catecholamine release from the midbrain to striatum and synapse formation between midbrain and striatal neurons. Moreover, Progerin-overexpressing assembloids acquire aging traits that lead to early phenotypes of PD. This new model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of PD.

neuroscience↗

bioRxiv2020

High Content Screening and Proteomic Analysis Identify the Kinase Inhibitor BX795 as a Potent Neuroprotective Compound in a Patient-Derived Model of Parkinson's Disease

Combining high throughput screening approaches with induced pluripotent stem cell (iPSC)-based disease modeling represents a promising unbiased strategy to identify therapies for neurodegenerative disorders. Here we applied high content imaging on iPSC-derived neurons from patients with familial Parkinsons disease bearing the G209A (p.A53T) -synuclein (Syn) mutation and launched a screening campaign on a small kinase inhibitor library. We thus identified the multi-kinase inhibitor BX795 that at a single dose effectively restores disease-associated neurodegenerative phenotypes. Proteomics profiling mapped the molecular pathways underlying the protective effects of BX795, comprising a cohort of 118 protein-mediators of the core biological processes of RNA metabolism, protein synthesis, modification and clearance, and stress response, all linked to the mTORC1 signaling hub. In agreement, expression of human p.A53T-Syn in neuronal cells affected key components of the mTORC1 pathway resulting in aberrant protein synthesis that was restored in the presence of BX795 with concurrent facilitation of autophagy. Taken together, we have identified a promising small molecule with neuroprotective actions as candidate therapeutic for PD and other protein conformational disorders.

neuroscience↗

bioRxiv2020

An original model of brain infection identifies B Streptococcus lipoprotein Blr as a ligand exploiting host endocytosis for blood-brain barrier crossing.

Pathogens able to cross the blood-brain barrier (BBB) induce long-term neurological sequelae and death. Understanding how neurotropic pathogens bypass this strong physiological barrier is a prerequisite to devise therapeutic strategies. Here we propose an innovative model of infection in the developing Drosophila brain, combining whole brain explants with in vivo systemic infection. We identified several mammalian pathogens able to cross the Drosophila BBB, including Group B Streptococcus (GBS). Amongst GBS surface components, lipoproteins, and in particular the B leucin-rich Blr, were important for BBB crossing and virulence in Drosophila. Further, we identified (V)LDL receptor LpR2, expressed in the BBB, as a host receptor for Blr, allowing GBS translocation through endocytosis. Finally, we demonstrated that Blr is required for BBB crossing and pathogenicity in a murine model of infection. Our results support the relevance of Drosophila for studying host-pathogen interactions and identify a new mechanism by which pathogens exploit host barriers to generate brain infection.

microbiology↗