Biology subjects

Byrne, A. B.

Publications and source records attributed to Byrne, A. B..

7 recordsLinked to original sources

bioRxiv2026

Nidogen/NID-1 guides regenerating motor axons in the mature nervous system

Restoring function to injured axons requires not only regeneration, but also accurate guidance and synapse reformation. Our understanding of how regenerating axons navigate the mature nervous system remains limited, as growth cones confront a cellular and molecular landscape distinct from development. Using Caenorhabditis elegans, we found that the basement membrane protein Nidogen (NID-1) promotes local guidance of regenerating motor axons in the mature nervous system by facilitating their growth alongside neighboring intact neuronal processes. Regenerating cholinergic axons preferentially track the branched dendrites of the PVD mechanosensory neuron or, in the absence of PVD dendrites, are guided alongside GABAergic commissures instead. Loss of nid-1 disrupts this guidance, reducing axon-PVD colocalization, increasing displacement from the pre-injury point of contact with the dorsal nerve cord, and disrupting synapse reformation and functional recovery. Tissue-specific rescue indicates that NID-1 expressed by body wall muscles or the hypodermis is sufficient to guide regenerating axons, whereas muscle-derived NID-1 is required to restore synapse reformation. Genetic data indicate that NID-1 function guides regenerating axons in coordination with laminin and integrin. Although this complex primarily directs cholinergic motor axons, ectopic integrin expression in GABAergic neurons is sufficient to reroute their regenerating axons alongside PVD dendrites in a NID-1-dependent manner. Together, these findings identify a NID-1-dependent post-developmental mechanism for directing regenerating axons and promoting functional repair.

neuroscience↗

bioRxiv2024

Comamonas aquatica inhibits TIR-1/SARM1 induced axon degeneration

Emerging evidence suggests the microbiome critically influences the onset and progression of neurodegenerative diseases; however, the identity of neuroprotective bacteria and the molecular mechanisms that respond within the host remain largely unknown. We took advantage of Caenorhabditis elegans well characterized nervous system and ability to eat uni-bacterial diets to determine how metabolites and neuroprotective molecules from single species of bacteria suppress degeneration of motor neurons. We found Comamonas aquatica significantly protects against degeneration induced by overexpressing a key regulator of axon degeneration, TIR-1/SARM1. Genetic analyses and metabolomics reveal Comamonas protects against neurodegeneration by providing sufficient Vitamin B12 to activate METR-1/MTR methionine synthase in the intestine, which then lowers toxic levels of homocysteine in TIR-1-expressing animals. Defining a molecular pathway between Comamonas and neurodegeneration adds significantly to our understanding of gut-brain interactions and, given the prominent role of homocysteine in neurodegenerative disorders, reveals how such a bacterium could protect against disease.

neuroscience↗

bioRxiv2024

Calibration of additional computational tools expands ClinGen recommendation options for variant classification with PP3/BP4 criteria

PurposeWe previously developed an approach to calibrate computational tools for clinical variant classification, updating recommendations for the reliable use of variant impact predictors to provide evidence strength up to Strong. A new generation of tools using distinctive approaches have since been released, and these methods must be independently calibrated for clinical application. MethodUsing our local posterior probability-based calibration and our established data set of ClinVar pathogenic and benign variants, we determined the strength of evidence provided by three new tools (AlphaMissense, ESM1b, VARITY) and calibrated scores meeting each evidence strength. Results All three tools reached the Strong level of evidence for variant pathogenicity and Moderate for benignity, though sometimes for few variants. Compared to previously recommended tools, these yielded at best only modest improvements in the tradeoffs of evidence strength and false positive predictions. ConclusionAt calibrated thresholds, three new computational predictors provided evidence for variant pathogenicity at similar strength to the four previously recommended predictors (and comparable with functional assays for some variants). This calibration broadens the scope of computational tools for application in clinical variant classification. Their new approaches offer promise for future advancement of the field.

bioinformatics↗

bioRxiv2023

PARP knockdown promotes synapse reformation after axon injury

Injured nervous systems are often incapable of self-repairing, resulting in permanent loss of function and disability. To restore function, a severed axon must not only regenerate, but must also reform synapses with target cells. Together, these processes beget functional axon regeneration. Progress has been made towards a mechanistic understanding of axon regeneration. However, the molecular mechanisms that determine whether and how synapses are formed by a regenerated motor axon are not well understood. Using a combination of in vivo laser axotomy, genetics, and high-resolution imaging, we find that poly (ADP-ribose) polymerases (PARPs) inhibit synapse reformation in regenerating axons. As a result, regenerated parp(-) axons regain more function than regenerated wild-type axons, even though both have reached their target cells. We find that PARPs regulate both axon regeneration and synapse reformation in coordination with proteolytic calpain CLP-4. These results indicate approaches to functionally repair the injured nervous system must specifically target synapse reformation, in addition to other components of the injury response.

neuroscience↗

bioRxiv2023

A single neuron in C. elegans orchestrates multiple motor outputs through parallel modes of transmission

Animals generate a wide range of highly coordinated motor outputs, which allows them to execute purposeful behaviors. Individual neuron classes in the circuits that generate behavior have a remarkable capacity for flexibility, as they exhibit multiple axonal projections, transmitter systems, and modes of neural activity. How these multi-functional properties of neurons enable the generation of highly coordinated behaviors remains unknown. Here we show that the HSN neuron in C. elegans evokes multiple motor programs over different timescales to enable a suite of behavioral changes during egg-laying. Using HSN activity perturbations and in vivo calcium imaging, we show that HSN acutely increases egg-laying and locomotion while also biasing the animals towards low-speed dwelling behavior over longer timescales. The acute effects of HSN on egg-laying and high-speed locomotion are mediated by separate sets of HSN transmitters and different HSN axonal projections. The long-lasting effects on dwelling are mediated by HSN release of serotonin that is taken up and re-released by NSM, another serotonergic neuron class that directly evokes dwelling. Our results show how the multi-functional properties of a single neuron allow it to induce a coordinated suite of behaviors and also reveal for the first time that neurons can borrow serotonin from one another to control behavior.

neuroscience↗

bioRxiv2022

Evidence-based calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for clinical use of PP3/BP4 criteria

Recommendations from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) for interpreting sequence variants specify the use of computational predictors as Supporting level of evidence for pathogenicity or benignity using criteria PP3 and BP4, respectively. However, score intervals defined by tool developers, and ACMG/AMP recommendations that require the consensus of multiple predictors, lack quantitative support. Previously, we described a probabilistic framework that quantified the strengths of evidence (Supporting, Moderate, Strong, Very Strong) within ACMG/AMP recommendations. We have extended this framework to computational predictors and introduce a new standard that converts a tools scores to PP3 and BP4 evidence strengths. Our approach is based on estimating the local positive predictive value and can calibrate any computational tool or other continuous-scale evidence on any variant type. We estimate thresholds (score intervals) corresponding to each strength of evidence for pathogenicity and benignity for thirteen missense variant interpretation tools, using carefully assembled independent data sets. Most tools achieved Supporting evidence level for both pathogenic and benign classification using newly established thresholds. Multiple tools reached score thresholds justifying Moderate and several reached Strong evidence levels. One tool reached Very Strong evidence level for benign classification on some variants. Based on these findings, we provide recommendations for evidence-based revisions of the PP3 and BP4 ACMG/AMP criteria using individual tools and future assessment of computational methods for clinical interpretation.

bioinformatics↗

bioRxiv2020

TIR-1/SARM1 Inhibits Axon Regeneration

An injured axon has two choices, regenerate or degenerate. In many neurons, the result is catastrophic axon degeneration and a failure to regenerate. To coerce the injured nervous system to regenerate, the molecular mechanisms that regulate both axon regeneration and degeneration need to be defined. We found that TIR-1/SARM1, a key regulator of axon degeneration, inhibits regeneration of injured motor axons. Loss of tir-1 function both reduces the frequency with which severed axon fragments degenerate and increases the frequency of axon regeneration. The increased regeneration in tir-1 mutants is not a secondary consequence of its effects on degeneration. Rather, TIR-1 carries out each of these opposing functions cell autonomously by regulating independent downstream genetic pathways. While promoting axon degeneration with the DLK-1 mitogen activated protein kinase (MAPK) signaling cascade, TIR-1 inhibits axon regeneration by activating the NSY-1/ASK1 MAPK signaling cascade. Our finding that TIR-1 regulates both axon regeneration and degeneration provides critical insight into how axons coordinately regulate the two key responses to injury, consequently informing approaches to manipulate the balance between these responses towards repair.

neuroscience↗