Biology subjects

Papassotiropoulos, A.

Publications and source records attributed to Papassotiropoulos, A..

4 recordsLinked to original sources

bioRxiv2025

Abnormal Tau Protein Influences Intercellular Mitochondrial Transfer Between Astrocytic and Neuronal Cells

Tauopathies are a group of neurodegenerative diseases characterized by the pathological accumulation of abnormal tau protein. A consequence of tau pathologies is mitochondrial dysfunctions, which affect essential processes such as mitochondrial transport, bioenergetics, and dynamics. Given the high energy demands of neurons, tau-induced mitochondrial impairment significantly contributes to neuronal vulnerability and degeneration. Recent studies have revealed that cells can transfer mitochondria between them to help energy-deficient cells. This process, known as intercellular mitochondrial transfer, occurs through two different pathways: an indirect transfer via extracellular vesicles and a direct transfer via tunneling nanotubes and gap junctions. Given the known impact of abnormal tau protein on mitochondrial transport and actin filament dynamics, we hypothesized that intercellular mitochondrial transfer could be altered in the context of tauopathies. Therefore, this study aimed to investigate mitochondrial transfer between astrocytic and neuronal cells and assess how abnormal tau protein may influence this process. Our results showed that abnormal tau protein enhances mitochondrial transfer from astrocytic to neuronal cells. Notably, this transfer occurs mainly via contact-dependent mechanisms. In both pathological and healthy conditions, the transferred astrocytic mitochondria either fused with the mitochondrial network of recipient cells or were degraded in the lysosomes or remained isolated in the cytosol. Our data highlight a novel pathway by which abnormal tau protein impacts mitochondrial function, namely the transfer of astrocytic mitochondria to neuronal cells.

neuroscience↗

bioRxiv2022

(-)-Gossypol inhibition of musashi-mediated forgetting improves memory and age-dependent memory decline in Caenorhabditis elegans

Musashi RNA-binding proteins retain a pivotal role in stem cell maintenance, tumorigenesis, and nervous system development. Recently, we showed in C. elegans that MSI1 actively promotes forgetting upon associative learning via a 3UTR-dependent translational expression of the Arp2/3 actin branching complex. Here, we investigated the evolutionary conserved role of MSI proteins and the effect of their pharmacological inhibition on memory. Expression of human MSI1 and MSI2 under the endogenous musashi promoter fully rescued the phenotype of msi-1(lf) worms. Furthermore, pharmacological inhibition of MSI1 and MSI2 activity using (-)-gossypol resulted in improved memory retention, without causing locomotor, chemotactic, or learning deficits. No drug effect was observed in msi-1(lf) treated worms. Using Western blotting and confocal microscopy we found no changes in MSI-1 protein abundance following (-)-gossypol treatment, suggesting that musashi gene expression remains unaltered and that the compound exerts its inhibitory effect post-translationally. Additionally, (-)-gossypol suppressed the previously seen rescue of the msi-1(lf) phenotype in worms expressing human MSI1 specifically in the AVA neuron, indicating that (-)-gossypol can regulate the musashi pathway in a memory-related neuronal circuit in worms. Finally, treating aged worms with (-)-gossypol reversed physiological age-dependent memory decline. Taken together, our findings indicate that pharmacological inhibition of musashi might represent a promising approach for memory modulation.

neuroscience↗

bioRxiv2018

Genetic control of variability in subcortical and intracranial volumes

Sensitivity to external demands is essential for adaptation to dynamic environments, but comes at the cost of increased risk of adverse outcomes when facing poor environmental conditions. Here, we apply a novel methodology to perform genome-wide association analysis of mean and variance in nine key brain features (accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, intracranial volume and cortical thickness), integrating genetic and neuroanatomical data from a large lifespan sample (n=25,575 individuals; 8 to 89 years, mean age 51.9 years). We identify genetic loci associated with phenotypic variability in cortical thickness, thalamus, pallidum, and intracranial volumes. The variance-controlling loci included genes with a documented role in brain and mental health and were not associated with the mean anatomical volumes. This proof-of-principle of the hypothesis of a genetic regulation of brain volume variability contributes to establishing the genetic basis of phenotypic variance (i.e., heritability), allows identifying different degrees of brain robustness across individuals, and opens new research avenues in the search for mechanisms controlling brain and mental health.

neuroscience↗

bioRxiv2018

Brain scans from 21297 individuals reveal the genetic architecture of hippocampal subfield volumes

The hippocampus is a heterogeneous structure, comprising histologically distinguishable subfields. These subfields are differentially involved in memory consolidation, spatial navigation and pattern separation, complex functions often impaired in individuals with brain disorders characterized by reduced hippocampal volume, including Alzheimers disease (AD) and schizophrenia. Given the structural and functional heterogeneity of the hippocampal formation, we sought to characterize the subfields genetic architecture. T1-weighted brain scans (n=21297, 16 cohorts) were processed with the hippocampal subfields algorithm in FreeSurfer v6.0. We ran a genome-wide association analysis on each subfield, covarying for total hippocampal volume. We further calculated the single nucleotide polymorphism (SNP)-based heritability of twelve subfields, as well as their genetic correlation with each other, with other structural brain features, and with AD and schizophrenia. All outcome measures were corrected for age, sex, and intracranial volume. We found 15 unique genome-wide significant loci across six subfields, of which eight had not been previously linked to the hippocampus. Top SNPs were mapped to genes associated with neuronal differentiation, locomotor behaviour, schizophrenia and AD. The volumes of all the subfields were estimated to be heritable (h2 from .14 to .27, all p< 1x10-16) and clustered together based on their genetic correlations compared to other structural brain features. There was also evidence of genetic overlap of subicular subfield volumes with schizophrenia. We conclude that hippocampal subfields have partly distinct genetic determinants associated with specific biological processes and traits. Taking into account this specificity may increase our understanding of hippocampal neurobiology and associated pathologies.

genetics↗