Biology subjects

Becker, C. G.

Publications and source records attributed to Becker, C. G..

18 recordsLinked to original sources

bioRxiv2026

Phyllosphere bacterial communities in milkweeds: composition diverge as the season progresses, and links to cardenolides and arthropods depend on host identity

Leaf bacterial communities shape plant defense and interactions with herbivores, yet how host filtering and stochastic processes assemble them remains unclear. We predicted that host identity, chemistry, and arthropods structure them, and that stochastic and deterministic contributions shift seasonally. Across one growing season we sampled leaf bacteria monthly and arthropods weekly on four Asclepias species (Apocynaceae: A. curassavica, A. incarnata, A. syriaca, A. tuberosa) spanning a cardenolide gradient. We sequenced 16S rRNA genes and quantified selection and dispersal contributions to turnover using null models. Host identity shaped bacterial richness and composition, with A. tuberosa hosting the richest communities, and both richness and phylogenetic diversity rose through the season. Early on, homogenizing dispersal made communities more similar among plants; by mid-season no single process dominated turnover, and by late season dispersal limitation prevailed. Homogeneous selection was episodic, not sustained, and arthropod associations were host-specific, negatively so on A. syriaca. Phyllosphere assembly thus shifts from convergence to divergence in one season: young leaves recruit from a shared pool delivered by wind, rain, and arthropods, whereas exchange among ageing plants declines and communities drift apart. Herbivores arriving late meet plant-specific microbial environments, so microbial mediation of herbivory should be host-specific and seasonally contingent.

ecology↗

bioRxiv2026

Baseline regulatory programs in larval and adult neural progenitors converge towards an injury-induced state after spinal cord injury

Regeneration after spinal cord injury requires progenitor cells to convert injury-associated signals into coordinated remodeling of gene regulatory programs. Mammalian spinal progenitors show limited neurogenic output after injury, whereas zebrafish regenerate spinal neurons and recover motor function. To investigate the regulatory changes that allow ependymo-radial glia (ERG) cells, the progenitor cells of the zebrafish spinal cord, to generate new neurons, we combined single-nucleus gene expression and chromatin accessibility profiling across embryonic, larval, and adult stages with topic-based gene regulatory network (GRN) inference. We found that larval and adult ERGs enter the injury response from distinct regulatory baselines: larval progenitors are characterized by a gliogenic program, whereas adult progenitors maintain a comparatively quiescent state. Following injury, both populations gradually change their baseline programs and shift towards a lesion-associated module marked by stress-responsive and chromatin-associated regulators, including jun, hmga1a, hmga2, ybx1, and foxj1a. The shift away from homeostatic states is supported by decreased expression of the Notch-associated regulators nuclear factor I A (nfia) and hey1 in larvae, while in adults, downregulation of the same nuclear factor and other TFs such as bhlhe41 is associated with quiescence exit. Pathway analysis showed stage-specific alterations after injury, characterized predominantly by extracellular signaling and cytoskeletal reorganization in larvae and by metabolic and translational remodeling in adults. Despite divergence from the homeostatic states, injury-induced larval and adult GRNs remain distinct from embryonic hERG regulatory programs. Thus, larval and adult progenitors follow different trajectories from their baselines towards a related lesion-reactive state, in which shared regeneration-associated features are acquired within respective contexts.

bioinformatics↗

bioRxiv2026

Diverse origins and transcriptional profiles of macrophages in a spinal lesion in zebrafish

The injury responses of tissue-resident macrophages in the CNS (microglia) and blood-derived macrophages (BDMs) play key roles in successful regeneration of the zebrafish spinal cord, but the origins and dynamic behaviours of these immune cells are not well characterized. Here, we find that microglia, labelled by the p2ry12:GFP reporter gene, migrate long-distance through neural tissue from the brain to the spinal lesion site, while BDMs, labelled by the mpeg1:mCherry reporter gene, migrate mainly from the caudal hematopoietic tissue to the lesion and back. Half of p2ry12:GFP-positive microglia co-express mpeg1:mCherry, while mpeg1:mCherry-positive BDMs are mostly p2ry12:GFP-negative. However, a BDM sub-population starts to express p2ry12:GFP in the lesion. This indicates heterogeneous and dynamic gene expression in macrophage populations. Gene expression profiling reveals several microglia-like and BDM-like clusters in the lesion with gene expression profiles related to proliferation, phagocytosis, pro- and anti-inflammatory phenotypes and distinct expression of regeneration-relevant genes. The most abundant cell cluster are densely-packed microglia-like cells in the lesion core, which express the novel marker g0s2, as well as phagocytosis-related genes. Hence, regenerative success of the zebrafish spinal cord is linked to a heterogeneous and dynamic response of microglia and BDM subpopulations.

neuroscience↗

bioRxiv2026

Spinal injury induces a stem cell-like progenitor state that promotes regenerative neurogenesis via clcf1 in zebrafish.

After spinal injury, zebrafish, in contrast to mammals, show regenerative neurogenesis, characterized by enhanced injury-induced proliferation of ependymo-radial glial cells (ERGs) and an increase in injury-induced generation of neurons from these progenitors. It is unclear whether regenerative neurogenesis simply recapitulates development or uses regeneration-specific mechanisms. Using scRNA-seq and in vivo validation we find a spinal injury-induced state in ERGs (iiERGs) in larval zebrafish. This cell state emerges mostly without proliferation and has stem cell characteristics, including weak expression of neurogenic genes and strong expression of stemness factors, such as lin28a. Expression of lin28a is not detectable during ongoing developmental neurogenesis. Following spinal cord lesion, lin28a disruption increases the numbers of ERGs undergoing neuronal differentiation and of newly-generated neurons, at the expense of proliferating ERGs and iiERGs. This supports a stemness-preserving role of lin28a in iiERGs. Importantly, iiERGs secrete growth factors, including the regeneration-specific cytokine clcf1, which depends in part on lin28a expression. Disruption of clcf1 signalling impairs spinal progenitor proliferation and injury-induced generation of new neurons, but does not affect the emergence of iiERGs. Over-expression of clcf1 is sufficient to augment neurogenesis in unlesioned animals without inducing the iiERG state, indicating that clcf1 acts as a generic growth factor. Hence, we describe an injury-specific stem cell-like ERG population that regulates regenerative neurogenesis by attenuating neuronal differentiation via lin28a and promoting progenitor proliferation via clcf1.

neuroscience↗

bioRxiv2026

Tachykinin neuropeptides are involved in axonal and synaptic differentiation of the pioneer motor axon in zebrafish

In contrast to many other developing systems, in which axon pathfinding and synaptogenesis are separated in time, the pioneering axon of the individually identifiable caudal primary motor neuron in embryonic zebrafish forms en passant synapses during its stereotypical ventral growth. How simultaneous synaptic differentiation and axon pathfinding are coordinated is not fully understood. Here we ask what the role of the tac1 gene, coding for the synaptic tachykinin neuropeptides, is in this unique axon differentiation process. The gene is expressed during axon outgrowth and its disruption results in increased branch length of CaP axons and subtle morphological defects of the pre-synapse. These abnormalities are accompanied by a robust [~]1.5-fold increase in motor neuron activity and in spontaneous early contractions in tac1-deficient embryos. Furthermore, pharmacological inhibition of the tachykinin receptor (Tacr1) leads to altered CaP axonal morphology, mimicking the axonal phenotype observed in tac1-deficient zebrafish. These findings suggest that tachykinin neuropeptides modulate formation and activity of en passant synapses and prevent aberrant axon branching during growth of zebrafish motor axons. HIGHLIGHTS- tac1 refines CaP primary motor axon development in zebrafish - Loss of tac1 disrupts presynaptic maturation at the horizontal myoseptum - tac1 mutants show elevated motor neuron activity and spontaneous contractions

neuroscience↗

bioRxiv2026

A reparative neutrophil subpopulation promotes spinal cord regeneration in zebrafish by controlling macrophage inflammation via Il-4

In mammals, a dysregulated immune response is detrimental to spinal cord repair. In zebrafish, which are capable of spinal cord regeneration, the immune response promotes regeneration. Neutrophils are the first immune cells to arrive at a spinal cord injury site, but their role in successful regeneration is not fully understood. Here we show that ablating neutrophils, including a subpopulation that expresses the cytokine il4, increases expression of il1b (coding for Il-1{beta}) in macrophages/microglia and impairs anatomical and functional recovery after a spinal cord injury in larval zebrafish. Regeneration is fully rescued by over-expression of il4 alone or experimentally reducing Il-1{beta} levels. Disruption of il4 mimics the detrimental effect of neutrophil ablation for axonal regeneration and is also rescued by reducing Il-1{beta} levels. Hence, after spinal cord injury, a pro-regenerative neutrophil subpopulation promotes spinal cord regeneration in larval zebrafish by controlling expression of il1b in macrophages/microglia. For this neutrophil action, il4 expression is necessary and sufficient. HIGHLIGHTS- Neutrophil ablation impairs spinal cord repair in zebrafish - The neutrophil response can be replaced by reducing Il-1{beta} levels - A pro-regenerative subpopulation of neutrophils expresses il4 - il4 overexpression fully rescues effects of neutrophil ablation

neuroscience↗

bioRxiv2025

Environmental Detection of the Amphibian Chytrid Fungus in Water Bodies Predicts Host Infection Along a Deforestation Gradient

Understanding pathogen dynamics during environmental life stages is vital for comprehending wildlife diseases, especially for those with a free-living phase. In amphibians affected by the chytrid fungus Batrachochytrium dendrobatidis (Bd), most studies have focused on host-pathogen interactions, with less emphasis on Bds environmental stage. We tested whether the distribution of Bd in natural aquatic environments can predict host infection patterns. We sampled four tropical amphibian species across eight rainforest landscapes with varying habitat loss, testing whether environmental and host Bd detection varied along gradients of habitat change. Using a high-capacity water filtration method coupled with digital and real-time PCR detection assays, we quantified Bd in water and amphibian samples. Our results revealed a strong positive correlation between Bd DNA concentrations in water samples and infection loads on amphibian skin samples. Forest cover and habitat split were the primary predictors of Bd distribution in both free-living and host-associated forms. We identified Bd-GPL and Bd-Asia-2/Brazil lineages across our study landscapes. Our study introduces and validates a robust protocol for detecting Bd in environmental samples, with the potential to enhance monitoring and inform management strategies. Moreover, our work contributes novel, well-replicated spatial data on Bd associations between hosts and their environments.

ecology↗

bioRxiv2025

Altered lysosomal biology impairs motor neuron survival via TFEB dysregulation in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a devastating motor neuron disease, caused by recessive mutations or deletions of the SMN1 gene, representing the leading genetic cause of infant mortality. Available therapies, aimed at increasing SMN protein levels, can only partially halt motor neuron (MN) degeneration in a select number of patients, reinforcing the need for combinatorial treatments to improve clinical outcomes. We previously showed that mTORC1 overactivation and impaired autophagosome clearance in SMA MNs lead to the accumulation of protein aggregates, contributing to MN degeneration. However, the mechanistic link between SMN protein deficiency and autophagy-lysosomal dysfunction remained unknown. Here, using patient iPSC-derived MNs along with isogenic and healthy controls, we show that SMA MNs exhibit reduced lysosome numbers and impaired functionality. Furthermore, the master regulator of lysosomal biogenesis and autophagy, TFEB, is downregulated, and its nuclear translocation compromised upon SMN deficiency. We further propose the upregulation of the mTORC1 positive modulator TPT1 as contributor to TFEB dysregulation. Notably, TFEB overexpression ameliorates protein aggregate accumulation in SMA MNs and enhances MN survival both in vitro and in a zebrafish SMA model. Our findings identify lysosomal dysfunction as a key player in SMA pathology and highlight TFEB activation as a potential therapeutic strategy for SMA treatment. One Sentence SummaryTFEB activation restores lysosomal function and improves motor neuron survival in SMA, highlighting its potential as a therapeutic target.

neuroscience↗

bioRxiv2024

Macrophage crosstalk with neural progenitors and fibroblasts controls regenerative neurogenesis via Sema4ab after spinal cord injury in zebrafish

Zebrafish, in contrast to mammals, regenerate neurons after spinal cord injury, but little is known about the control mechanisms of this process. Here we use scRNA-seq and in vivo experiments to show that sema4ab, mainly expressed by lesion-reactive microglia, attenuates regenerative neurogenesis by changing the complex lesion environment. After spinal injury, disruption of sema4ab doubles the number of newly generated progenitor cells and neurons but attenuates axon regrowth and recovery of swimming function. Disruption of the plxnb1a/b receptors, selectively expressed by neural progenitor cells, increases regenerative neurogenesis. In addition, disruption of sema4ab alters activation state and cytokine expression of microglia, such that fibroblasts increase expression of the cytokine tgfb3, which strongly promotes regenerative neurogenesis. Hence, sema4ab in microglia attenuates regenerative neurogenesis in multiple ways, likely directly through plxnb1a/b receptors and indirectly, by controlling the inflammatory milieu and tgfb3 levels. Targeting Sema4A-dependent signalling in non-regenerating vertebrates may be a future strategy to improve regenerative outcomes. HIGHLIGHTS- Microglia suppress pro-regenerative fibroblast signalling in a spinal injury site - Fibroblasts promote regenerative neurogenesis via Tgfb3 signalling - sema4ab promotes microglia activation state after spinal injury - scRNA-seq reveals full complement of sema4ab-dependent changes on different cell types during repair of a spinal lesion site

neuroscience↗

bioRxiv2024

Do fungi look like macroparasites? Quantifying the patterns and mechanisms of aggregation for host-fungal parasite relationships

Most hosts contain few parasites, whereas few hosts contain many. This pattern, known as aggregation, is well-documented in macroparasites where parasite intensity distribution among hosts affects host-parasite dynamics. Infection intensity also drives fungal disease dynamics, but we lack a basic understanding of host-fungal aggregation patterns, how they compare to macroparasites, and if they reflect biological processes. To address these gaps, we characterized aggregation of the fungal pathogen Batrachochytrium dendrobatidis (Bd) in amphibian hosts. Utilizing the slope of Taylors Power Law, we found Bd intensity distributions were more aggregated than macroparasites, conforming closely to lognormal distributions. We observed that Bd aggregation patterns are strongly correlated with known biological processes operating in amphibian populations, such as epizoological phase--invasion, post-invasion, and enzootic--and intensity-dependent disease mortality. Using intensity-dependent mathematical models, we found evidence of evolution of host resistance based on aggregation shifts in systems persisting with Bd following disease-induced declines. Our results show that Bd aggregation is highly conserved across disparate systems and is distinct from aggregation patterns in macroparasites, and contains signatures of potential biological processes of amphibian-Bd systems. Our work lays a foundation to unite host-fungal dynamics under a common theoretical framework and inform future modeling approaches that may elucidate host-fungus interactions.

ecology↗

bioRxiv2024

Wound closure after brain injury relies on force generation by microglia in zebrafish

Wound closure after a brain injury is critical for tissue restoration but this process is still not well characterised at the tissue level. We use live observation of wound closure in larval zebrafish after inflicting a stab wound to the brain. We demonstrate that the wound closes in the first 24 hours after injury by global tissue contraction. Microglia accumulation at the point of tissue convergence precedes wound closure and computational modelling of this process indicates that physical traction by microglia could lead to wound closure. Indeed, genetically or pharmacologically depleting microglia leads to defective tissue repair. Live observations indicate centripetal deformation of astrocytic processes contacted by migrating microglia. Severing such contacts leads to retraction of cellular processes, indicating tension. Weakening tension by disrupting the F-actin stabilising gene lcp1 in microglial cells, leads to failure of wound closure. Therefore, we propose a previously unidentified mechanism of brain repair in which microglia has an essential role in contracting spared tissue. Understanding the mechanical role of microglia will support advances in traumatic brain injury therapies Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=191 HEIGHT=200 SRC="FIGDIR/small/597300v3_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@112aorg.highwire.dtl.DTLVardef@6712c4org.highwire.dtl.DTLVardef@101179borg.highwire.dtl.DTLVardef@b4ecb6_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

C9ORF72 deficiency results in degeneration of the zebrafish retina in vivo

G4C2 Hexanucleotide repeat expansions within the gene C9ORF72 are the most common cause of the neurodegenerative diseases Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD). This disease-causing expansion leads to a reduction in C9ORF72 expression levels in patients, suggesting haploinsufficiency could contribute to disease. To further understand the consequences of C9ORF72 deficiency in vivo, we generated a c9orf72 mutant zebrafish line. Analysis of the spinal cord revealed no appreciable neurodegenerative pathology such as loss of motor neurons, or increased levels of neuroinflammation. However, detailed examination of c9orf72-/- retinas showed prominent neurodegenerative features, including a decrease in retinal thickness, gliosis, and an overall reduction in neurons of all subtypes. Structurally, analysis of rod and cone cells within the photoreceptor layer showed a disturbance in the outer cells of the retina and rhodopsin mis-localisation from rod outer segments to their cell bodies and synaptic endings. Thus, C9ORF72 may play a previously unappreciated role in retinal homeostasis and suggests C9ORF72 deficiency can induce tissue specific neuronal loss.

neuroscience↗

bioRxiv2022

Comparative host-pathogen dynamics of Snake Fungal Disease in sympatric species of water snakes (Nerodia)

The ascomycete fungus Ophidiomyces ophiodiicola (Oo) is the causative agent of ophidiomycosis (Snake Fungal Disease), which has been detected globally. However, surveillance efforts in the central U.S., specifically Texas, have been minimal. The threatened and rare Brazos water snake (Nerodia harteri harteri) is one of the most range restricted snakes in the U.S. and is sympatric with two wide-ranging congeners, N. erythrogaster transversa and N. rhombifer, in north central Texas; thus, providing an opportunity to test comparative host-pathogen dynamics in this system. To accomplish this, we surveyed a portion of the Brazos river drainage (~400 river km) over 29 months and tested 150 Nerodia spp. for the presence of Oo via quantitative PCR and recorded any potential signs of Oo infection. We found Oo was distributed across the entire range of N. h. harteri, Oo prevalence was 46 % overall, and there was a significant association between Oo occurrence and signs of infection in our sample. Models indicated adults had a higher probability of Oo infection than juveniles and subadults, and adult N. h. harteri had a higher probability of infection than adult N. rhombifer but not higher than adult N. e. transversa. High Oo prevalence estimates (94.4%) in adult N. h. harteri has implications for their conservation and management owing to their patchy distribution, comparatively low genetic diversity, and threats from anthropogenic habitat modification.

ecology↗

bioRxiv2021

Host immune responses to enzootic and invasive pathogen lineages vary in magnitude, timing, and efficacy

Infectious diseases of wildlife continue to pose a threat to biodiversity worldwide, yet pathogens are far from monolithic in virulence. Within the same pathogen species, virulence can vary considerably depending on strain or lineage, in turn eliciting variable host responses. One pathogen that has caused extensive biodiversity loss is the amphibian-killing fungus, Batrachochytrium dendrobatidis (Bd), which is comprised of a globally widespread hypervirulent lineage (Bd-GPL), and multiple geographically restricted lineages. Whereas host immunogenomic responses to Bd-GPL have been characterized in a number of amphibian species, immunogenomic responses to geographically-restricted, enzootic Bd lineages are unknown. To examine lineage- specific host immune responses to Bd, we exposed a species of pumpkin toadlet, Brachycephalus pitanga, which is endemic to Brazils Southern Atlantic Forest, to either the Bd-GPL or the enzootic Bd-Asia-2/Brazil (hereafter Bd-Brazil) lineage. We quantified functional immunogenomic responses over the course of infection using differential gene expression tests and coexpression network analyses. Host immune responses varied significantly with Bd lineage. Toadlet responses to Bd-Brazil were weak at early infection (26 genes differentially expressed), peaked by mid-stage infection (435 genes) and were nearly fully resolved by late-stage disease (9 genes). In contrast, responses to Bd-GPL were magnified and delayed; toadlets differentially expressed 97 genes early, 86 genes at mid-stage infection, and 728 genes by late-stage infection. Given that infection intensity did not vary between mid- and late-stage disease, this suggests that pumpkin toadlets may be at least partially tolerant to the geographically-restricted Bd- Brazil lineage. In contrast, mortality was higher in Bd-GPL-infected toadlets, suggesting that late-stage immune activation against Bd-GPL was not protective and was consistent with immune dysregulation previously observed in other species. Our results demonstrate that both the timing of immune response and the particular immune pathways activated are specific to Bd lineage. Within regions where multiple Bd lineages co-occur, and given continued global Bd movement, these differential host responses may influence not only individual disease outcome, but transmission dynamics at the population and community levels.

genomics↗

bioRxiv2020

Phenotypic screening using synthetic CRISPR gRNAs reveals pro-regenerative genes in spinal cord injury

Acute CRISPR/Cas9 targeting offers the opportunity for scalable phenotypic genetic screening in zebrafish. However, the unpredictable efficiency of CRISPR gRNA (CrRNA) activity is a limiting factor. Here we describe how to resolve this by prescreening CrRNAs for high activity in vivo, using a simple standardised assay based on restriction fragment length polymorphism analysis (RFLP). We targeted 350 genomic sites with synthetic RNA Oligo guide RNAs (sCrRNAs) in zebrafish embryos and found that almost half exhibited > 90% efficiency in our RFLP assay. Having the ability to preselect highly active sCrRNAs (haCRs), we carried out a focussed phenotypic screen of 30 macrophage-related genes in spinal cord regeneration and found 10 genes whose disruption impaired axonal regeneration. Four (tgfb1a, tgfb3, tnfa, sparc) out of 5 stable mutants subsequently analysed retained the acute haCR phenotype, validating the efficiency of this approach. Mechanistically, lack of tgfb1a leads to a prolonged immune response after injury, which inhibits regeneration. Our rapid and scalable screening approach has identified functional regulators of spinal cord regeneration, and can be applied to study any biological function of interest. HIGHLIGHTS- Synthetic CRISPR gRNAs are highly active - in vivo pre-screening allows rapid assessment of CRISPR gRNA activity - Phenotypic CRISPR screen reveals crucial genes for spinal cord regeneration - tgfb1a promotes spinal regeneration by controlling inflammation

neuroscience↗

bioRxiv2018

Regeneration of dopaminergic neurons in adult zebrafish depends on immune system activation and differs for distinct populations

Adult zebrafish regenerate neurons in their brain, but the extent and variability of this capacity is unclear. Here we ask whether loss of various dopaminergic neuron populations is sufficient to trigger their functional regeneration. Genetic lineage tracing shows that specific diencephalic ependymo-radial glial progenitor cells (ERGs) give rise to new dopaminergic (Th+) neurons. Ablation elicits an immune response, increased proliferation of ERGs and increased addition of new Th+ neurons in populations that constitutively add new neurons, e.g. diencephalic population 5/6. Inhibiting the immune response attenuates neurogenesis to control levels. Boosting the immune response enhances ERG proliferation, but not addition of Th+ neurons. In contrast, in populations in which constitutive neurogenesis is undetectable, e.g. the posterior tuberculum and locus coeruleus, cell replacement and tissue integration are incomplete and transient. This is associated with loss of spinal Th+ axons, as well as permanent deficits in shoaling and reproductive behaviour. Hence, dopaminergic neuron populations in the adult zebrafish brain show vast differences in regenerative capacity that correlate with constitutive addition of neurons and depend on immune system activation.

neuroscience↗

bioRxiv2018

Dynamic control of proinflammatory cytokines Il-1β and Tnf-α by macrophages is necessary for functional spinal cord regeneration in zebrafish

Spinal cord injury leads to a massive response of innate immune cells (microglia, macrophages, neutrophils) both, in non-regenerating mammals and in successfully regenerating zebrafish, but the role of these immune cells in functional spinal cord regeneration in zebrafish has not been addressed. Here we show that inhibiting inflammation reduces and promoting it accelerates axonal regeneration in larval zebrafish. Mutant analyses show that peripheral macrophages, but not neutrophils or microglia, are necessary and sufficient for full regeneration. Macrophage-less irf8 mutants show prolonged inflammation with elevated levels of Il-1{beta} and Tnf-. Decreasing Il-1{beta} levels or number of Il-1{beta}+ neutrophils rescues functional regeneration in irf8 mutants. However, during early regeneration, interference with Il-1{beta} function impairs regeneration in irf8 and wildtype animals. Inhibiting Tnf- does not rescue axonal growth in irf8 mutants, but impairs it in wildtype animals, indicating a pro-regenerative role of Tnf-. Hence, inflammation is tightly and dynamically controlled by macrophages to promote functional spinal cord regeneration in zebrafish.

developmental biology↗

bioRxiv2017

A novel mitochondrial enriched antioxidant protects neurons against acute oxidative stress

Excessive reactive oxygen species (ROS) can damage proteins, lipids, and DNA, which result in cell damage and death. The outcomes can be acute, as seen in stroke, or more chronic as observed in age-related diseases such as Parkinsons disease. Here we investigate the antioxidant ability of a novel synthetic flavonoid, Proxison (7-decyl-3-hydroxy-2-(3,4,5-trihydroxyphenyl)-4-chromenone), using a range of in vitro and in vivo approaches. We show that, while it has radical scavenging ability on par with other flavonoids in a cell-free system, Proxison is orders of magnitude more potent than natural flavonoids at protecting neural cells against oxidative stress and is capable of rescuing damaged cells. The unique combination of a lipophilic hydrocarbon tail with a modified polyphenolic head group promotes efficient cellular uptake and mitochondrial localisation of Proxison. Importantly, in vivo administration of Proxison demonstrated effective and well tolerated neuroprotection against oxidative stress in a zebrafish model of dopaminergic neuronal loss.

cell biology↗