Biology subjects

Eugenin von Bernhardi, J.

Publications and source records attributed to Eugenin von Bernhardi, J..

3 recordsLinked to original sources

bioRxiv2025

Myelin density dictates region-specific vulnerability of oligodendrocyte lineage cells during aging

Aging of the central nervous system (CNS) leads to a progressive decline in numerous physiological functions. This decline can be attributed in part to alterations within the oligodendrocyte lineage, which comprises myelinating oligodendrocytes (OLs) and their progenitors, NG2-glia, that play a central role in maintaining homeostasis and ensuring proper myelin turnover. While NG2-glia are distributed throughout the CNS, OLs are enriched in highly myelinated regions, implying spatially heterogeneous requirements for NG2-glia proliferation and differentiation. Consequently, age-related impairments in these progenitor functions may differentially compromise oligodendrogenesis and myelin maintenance across distinct CNS compartments. Yet, the spatial and temporal dynamics of aging-associated alterations within the oligodendrocyte lineage remains insufficiently characterized. To address this gap, we investigated the effects of aging across three age groups in two anatomically adjacent but functionally distinct CNS regions, the cortical gray matter (GM) and the corpus callosum (CC). We demonstrated that aging is accompanied by a marked decline in the NG2-glia population. Aging NG2-glia displayed cell cycle dysregulation, characterized by reduced proliferative and differentiative capacity and accompanied by increased expression of cyclin-dependent kinase inhibitors (CDKIs), indicating disrupted homeostatic regulation. These alterations were most pronounced in highly myelinated regions, which also exhibited a stronger shift toward an age-associated inflammatory milieu. In parallel, we observed substantial accumulation of myelin debris and impaired phagocytic clearance in these myelin-dense areas. Moreover, we identified a selective loss of myelinating OLs in the CC, a phenomenon not detected in the gray matter (GM). Together, our findings delineate a tight interdependence between regional myelin density, inflammatory status, and the vulnerability of oligodendrocyte lineage cells to aging. These highlight multiple entry points of potential therapeutic intervention to mitigate CNS aging.

neuroscience↗

bioRxiv2025

ATXN2 polyglutamine expansion impairs QKI-dependent alternative splicing and oligodendrocyte maintenance

BackgroundPolyglutamine (polyQ) tract expansion mutations in Ataxin-2 gene (ATXN2) are associated with neurodegenerative diseases spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS), while the therapeutic reduction of ATXN2 confers strong health-/lifespan extension in models of both disorders. Although the involvement of ATXN2 in peripheral lipid metabolism has been elaborated in Atxn2 knock-out mice, its impact on nervous system lipid maintenance and a potential influence on oligodendrocytes remains unexplored. MethodsWe examine the nervous tissue of an authentic ATXN2 polyQ expansion mouse model in terms of (i) gross morphology of the brain and differential glial affection via immunohistochemical analyses, (ii) spinocerebellar proteome profile via label-free mass spectroscopy and (iii) alternative splicing patterns of oligodendroglial transcripts via quantitative RT-PCR. Finally, electrophysiological recording of sensory response in cerebellar Purkinje cells was performed as a phenotypic measure of demyelination. ResultsWe demonstrate a massive impairment in myelin maintenance due to ATXN2 polyQ expansion, affecting key oligodendroglial proteins accompanied by their splicing anomalies much earlier than disease manifestation. Oligodendroglial ATXN2 aggregates were documented for the first time in cerebellum, which sequestrated the RNA splicing factor Quaking (QKI). As an outcome of demyelination, our SCA2 model showed a significant delay in response to sensory stimuli. ConclusionsOverall, we provide pioneer evidence of oligodendroglial proteotoxicity leading to myelin maintenance defects in an authentic mouse model of SCA2. Our findings suggest that not only neuronal metabolism, but also that of oligodendroglia depends on ATXN2 and is affected during the disease course. This novel aspect of ATXN2 pathomechanism sheds light on potential outcomes of its therapeutic manipulation, and makes it relevant also for demyelination syndromes next to SCA2 and other polyQ disorders.

neuroscience↗

bioRxiv2024

Brain-wide mapping of oligodendrocyte organization and oligodendrogenesis across the murine lifespan

Insulating sheaths of myelin accelerate neuronal signaling in complex networks of the mammalian brain. In the CNS, myelin sheaths are exclusively produced by oligodendrocytes, which continue to be generated throughout life to change patterns of myelination. However, a brain-wide analysis of oligodendrocyte dynamics across the lifespan has not been performed. We developed a rapid, robust cellular mapping pipeline involving tissue clearing, lightsheet microscopy, atlas alignment, and automated segmentation to define the location of all oligodendrocytes in the mouse brain. This analysis demonstrated the remarkable consistency of oligodendrocyte patterns between hemispheres, individuals, and sexes, and established that oligodendrocyte maps estimate myelin coverage. We trained a vision transformer to identify newly generated oligodendrocytes from millions of mature cells, highlighting age- and region-specific differences in oligodendrogenesis, and revealing areas of enhanced oligodendrocyte resilience and regenerative capacity following demyelination, demonstrating the utility of this pipeline for uncovering brain-wide oligodendrocyte dynamics in health and disease.

neuroscience↗