Biology subjects

Bergmans, S.

Publications and source records attributed to Bergmans, S..

5 recordsLinked to original sources

bioRxiv2025

Differential retinal ganglion cell resilience to optic nerve injury across vertebrate species

Optic neuropathies comprise a diverse group of disorders that ultimately lead to retinal ganglion cell (RGC) degeneration. Despite varying etiologies, these conditions share a conserved pathological progression: axonal damage in the optic nerve triggers progressive RGC degeneration. Understanding species-specific differences in neuronal resilience is critical for identifying key survival mechanisms and potential neuroprotective targets. In this study, we compare RGC densities and survival rates following optic nerve crush (ONC) in three vertebrate models--mice, zebrafish, and killifish--under standardized experimental conditions. Transcriptomic analysis confirmed that, similar to RBPMS in mice, Rbpms2 serves as a pan-RGC marker in zebrafish and killifish. Using these markers, we reveal significant species-specific differences in RGC density, with fish species exhibiting over a five-fold higher density than mice at equivalent life stage. Killifish also show an age-dependent decline in RGC density. Furthermore, we identify distinct injury responses across species: mice undergo rapid degeneration, losing [~]80% of their RGCs by day 14 after ONC; zebrafish maintain full RGC retention for two weeks before experiencing a loss of [~]12%; and killifish display a biphasic response to ONC, with young adults retaining two-thirds of their RGCs by day 21, while older fish exhibit a more pronounced second wave of RGC loss, ultimately preserving just over half of their RGCs by 21 days after injury. These findings highlight fundamental differences in neuroprotective capacity among species, providing a comparative framework to uncover molecular mechanisms governing RGC survival and to identify therapeutic strategies for treating optic neuropathies and neurodegeneration across diverse pathologies.

neuroscience↗

bioRxiv2025

Successful axonal regeneration is driven by evolutionarily conserved metabolic reprogramming

Unlike mammals, zebrafish can regrow axons after injury and restore circuit function in the central nervous system (CNS). Mitochondria have been identified as key players in this process, but how different metabolic pathways work together to sustain regeneration remains unclear. Using RNA sequencing of adult zebrafish retinal ganglion cells after optic nerve crush injury, we found that oxidative phosphorylation is downregulated during axonal regrowth. Simultaneously, the thioredoxin antioxidant system was upregulated, likely to limit oxidative damage. Additionally, we observed an integrated upregulation of glycolysis and the pentose phosphate pathway during the initial regrowth phases, possibly to provide energy and supplying NADPH for biosynthesis and antioxidant responses. We show that this metabolic reprogramming is evolutionarily conserved, as a comparable one occurs in the pro-regenerative mammalian Pten and Socs3 co-deletion model. Inhibiting glycolysis and thioredoxin in zebrafish impairs axonal regrowth, suggesting that targeting these pathways could enhance CNS regeneration in mammals.

neuroscience↗

bioRxiv2024

A deep phenotyping study in mouse and iPSC models to understand the role of oligodendroglia in optic neuropathy in Wolfram syndrome

Wolfram syndrome (WS) is a rare childhood disease characterized by diabetes mellitus, diabetes insipidus, blindness, deafness, neurodegeneration and eventually early death, due to autosomal recessive mutations in the WFS1 (and WFS2) gene. While it is categorized as a neurodegenerative disease, it is increasingly becoming clear that other cell types besides neurons may be affected and contribute to the pathogenesis. MRI studies in patients and phenotyping studies in WS rodent models indicate white matter/myelin loss, implicating a role for oligodendroglia in WS-associated neurodegeneration. In this study, we sought to determine if oligodendroglia are affected in WS and whether their dysfunction may be the primary cause of the observed optic neuropathy and brain neurodegeneration. We demonstrate that 7.5-month-old Wfs1{Delta}exon8 mice display signs of abnormal myelination and a reduced number of oligodendrocyte precursor cells (OPCs) as well as abnormal axonal conduction in the optic nerve. An MRI study of the brain furthermore revealed grey and white matter loss in the cerebellum, brainstem, and superior colliculus, as is seen in WS patients. To further dissect the role of oligodendroglia in WS, we performed a transcriptomics study of WS patient iPSC-derived OPCs and pre-myelinating oligodendrocytes. Transcriptional changes compared to isogenic control cells were found for genes with a role in ER function. However, a deep phenotyping study of these WS patient iPSC-derived oligodendroglia unveiled normal differentiation, mitochondria-associated endoplasmic reticulum (ER) membrane interactions and mitochondrial function, and no overt signs of ER stress. Overall, the current study indicates that oligodendroglia functions are largely preserved in the WS mouse and patient iPSC-derived models used in this study. These findings do not support a major defect in oligodendroglia function as the primary cause of WS, and warrant further investigation of neurons and neuron-oligodendroglia interactions as a target for future neuroprotective or -restorative treatments for WS.

neuroscience↗

bioRxiv2024

Age-related dysregulation of the retinal transcriptome in African turquoise killifish

Age-related vision loss caused by retinal neurodegenerative pathologies is becoming more prevalent in our ageing society. To understand the physiological and molecular impact of ageing on retinal homeostasis, we used the short-lived African turquoise killifish, a model known to naturally develop central nervous system (CNS) ageing hallmarks and vision loss. Bulk and single-cell RNA-sequencing (scRNA-seq) of three age groups (6-, 12-, and 18-week-old) identified transcriptional ageing fingerprints in the killifish retina, unveiling pathways also identified in the aged brain, including oxidative stress, gliosis, and inflammageing. These findings were comparable to observations in ageing mouse retina. Additionally, transcriptional changes in genes related to retinal diseases, such as glaucoma and age-related macular degeneration, were observed. The cellular heterogeneity in the killifish retina was characterised, confirming the presence of all typical vertebrate retinal cell types. Data integration from age-matched samples between the bulk and scRNA-seq experiments revealed a loss of cellular specificity in gene expression upon ageing, suggesting potential disruption in transcriptional homeostasis. Differential expression analysis within the identified cell types highlighted the role of glial/immune cells as important stress regulators during ageing. Our work emphasises the value of the fast-ageing killifish in elucidating molecular signatures in age-associated retinal disease and vision decline. This study contributes to the understanding of how age-related changes in molecular pathways may impact CNS health, providing insights that may inform future therapeutic strategies for age-related pathologies. HighlightsO_LIThe aged killifish retina displays several ageing hallmarks, such as oxidative stress, gliosis and inflammageing, at the transcriptome level. C_LIO_LIRisk genes for neurodegenerative disorders show dysregulation in the old killifish retina. C_LIO_LIAll vertebrate retinal cell types are present in the killifish retina. C_LIO_LITranscriptional dysregulation in the aged killifish retina is observed across cell types. C_LI

neuroscience↗

bioRxiv2024

Local glycolysis supports injury-induced axonal regeneration

Successful axonal regeneration following injury requires the effective allocation of energy. Mitochondria play a pivotal role, accumulating at the tips of growing axons to fuel regeneration. However, how axons withstand the initial disruption in mitochondrial energy production caused by the injury, and subsequently initiate regrowth is poorly understood. Using retinal cultures in a multicompartment microfluidic device, we observed increased regrowth and enhanced mitochondrial trafficking in the axons of retinal ganglion cells with the deletion of both Pten and Socs3. While wild-type axons relied on mitochondrial metabolism, after injury, in the absence of Pten and Socs3, energy production was demonstrated to be supported by local glycolysis. Slowing down glycolysis in these axons impaired both regrowth and energy production. Together, these observations reveal that glycolytic ATP, combined with sustained mitochondrial transport, is essential for injury-induced axonal regrowth, providing new insights into the metabolic underpinnings of axonal regeneration.

neuroscience↗