Biology subjects

Thackeray, A.

Publications and source records attributed to Thackeray, A..

3 recordsLinked to original sources

bioRxiv2025

Remodeling of extracellular matrix collagen IV by MIG-6/papilin regulates neuronal architecture

Neuronal architecture established embryonically must persist lifelong to ensure normal brain function. However, little is understood about the mechanisms behind the long-term maintenance of neuronal organization. To uncover maintenance mechanisms, we performed a suppressor screen in sax-7/L1CAM mutants, which exhibit progressive disorganization with age. We identified the conserved extracellular matrix protein MIG-6/papilin as a key regulator of neuronal maintenance. Combining incisive molecular genetics, structural predictions, in vivo quantitative imaging, and cutting-edge Brillouin microscopy, we show that MIG-6/papilin remodels extracellular matrix collagen IV, working in concert with the secreted enzymes MIG-17/ADAMTS and PXN-2/peroxidasin. This remodeling impacts tissue biomechanics and ensures neuronal stability, even under increased mechanical stress. Our findings highlight an extracellular mechanism by which MIG-6/papilin supports the integrity of neuronal architecture throughout life. This work provides critical insights into the molecular basis of sustaining neuronal architecture and offers a foundation for understanding age-related and neurodegenerative disorders.

developmental biology↗

bioRxiv2025

VPS13D mutations disrupt mitochondrial homeostasis and locomotion in Caenorhabditis elegans

Mitochondria control cellular metabolism, serve as hubs for signaling and organelle communication, and are important for the health and survival of cells. VPS13D encodes a cytoplasmic lipid transfer protein that regulates mitochondrial morphology, mitochondria and endoplasmic reticulum (ER) contact, quality control of mitochondria. VPS13D mutations have been reported in patients displaying ataxic and spastic gait disorders with variable age of onset. Here we used CRISPR/Cas9 gene editing to create VPS13D related-spinocerebellar ataxia-4 (SCAR4) missense mutations and C-terminal deletion in VPS13Ds orthologue vps-13D in C. elegans. Consistent with SCAR4 patient movement disorders and mitochondrial dysfunction, vps-13D mutant worms exhibit locomotion defects and abnormal mitochondrial morphology. Importantly, animals with a vps-13D deletion or a N3017I missense mutation exhibited an increase in mitochondrial unfolded protein response (UPRmt). The cellular and behavioral changes caused by VPS13D mutations in C. elegans advance the development of animal models that are needed to study SCAR4 pathogenesis.

genetics↗

bioRxiv2022

Vitamin B12 produced by gut bacteria modulates excitatory neurotransmission

A growing body of evidence indicates that gut microbiota influence brain function and behavior. However, the molecular basis of how gut bacteria modulate host nervous system function is largely unknown. Here we show that vitamin B12-producing bacteria that colonize the intestine can modulate excitatory synaptic transmission and behavior in the host Caenorhabditis elegans. We find that vitamin B12 reduces cholinergic signaling in the nervous system through rewiring of the methionine (Met)/S-Adenosylmethionine (SAM) cycle in the intestine. We identify a conserved metabolic crosstalk between the Met/SAM cycle and the choline oxidation pathway. We show that metabolic rewiring of these pathways by vitamin B12 reduces cholinergic transmission by limiting the availability of free choline required by neurons to synthesize acetylcholine. Our study reveals a gut-brain communication pathway by which enteric bacteria modulate host behavior and may affect mental health.

neuroscience↗