Driscoll, H. E. | bioRxiv Science

bioRxiv2026

Giant spider neurons uncover a myelin-derived waste-internalizing canal system that fails in neurodegeneration

The underlying causes for Alzheimer disease are presumed to lie in failed waste removal from the brain. However, the mechanisms by which waste is cleared from neurons, and how this system fails in neurodegeneration are poorly understood. A novel glial-canal-hypothesis postulates that myelin-forming macroglia give rise to waste internalizing canals that project into neuronal somata and remove cellular debris in an aquaporin4-dependent manner. We postulate that abnormal swelling of the aquaporin4-expressing glial cells leads to spongiform abnormalities, gradual depletion, and death of associated neurons. Due to the novelty of this postulation little is known about the cellular architecture of this canal system that was first discovered in giant neurons of the wandering spider Cupiennius salei. Here we have utilized histological, ultrastructural and immunohistochemical methods to describe the structural foundation of this glial canal system in giant spider neurons in which waste-internalizing canals and associated structures are clearly visible. Sequencing the spider genome, we show compelling homologies of key proteins that are implicated in neurodegeneration between phylogenetically distant species. Based on this work, we provide a testable functional hypothesis regarding waste removal from neuronal somata and how this system fails in neurodegeneration. We highlight structural similarities of this system in rodent and human brain. Supported by the findings presented here we postulate that (i) neurodegeneration in C. salei may be caused by hypertrophic swelling of myelin-forming waste-internalizing macroglia, and (ii) that a similar canal system, although structurally modified, is likely highly conserved in the mammalian brain.

neuroscience↗

bioRxiv2023

Small regulatory RNAs are mediators of the Streptococcus mutans SloR regulon

Dental caries is among the most prevalent chronic infectious diseases worldwide. Streptococcus mutans, the chief causative agent of caries, uses a 25 kDa manganese dependent SloR protein to coordinate the uptake of essential manganese with the transcription of its virulence attributes. Small non-coding RNAs (sRNAs) can either enhance or repress gene expression and reports in the literature ascribe an emerging role for sRNAs in the environmental stress response. Herein, we identify 18-50 nt sRNAs as mediators of the S. mutans SloR and manganese regulons. Specifically, the results of sRNA-seq revealed 56 sRNAs in S. mutans that were differentially transcribed in the SloR-proficient UA159 and SloR-deficient GMS584 strains, and 109 sRNAs that were differentially expressed in UA159 cells grown in the presence of low versus high manganese. We describe SmsR1532 and SmsR1785 as SloR- and/or manganese-responsive sRNAs that are processed from large transcripts, and that bind SloR directly in their promoter regions. The predicted targets of these sRNAs include regulators of metal ion transport, growth management via a toxin-antitoxin operon, and oxidative stress tolerance. These findings support a role for sRNAs in coordinating intracellular metal ion homeostasis with virulence gene control in an important oral cariogen. IMPORTANCESmall regulatory RNAs (sRNAs) are critical mediators of environmental signaling, particularly in bacterial cells under stress, but their role in Streptococcus mutans is poorly understood. S. mutans, the principal causative agent of dental caries, uses a 25 kDa manganese-dependent protein, called SloR, to coordinate the regulated uptake of essential metal ions with the transcription of its virulence genes. In the present study, we identified and characterize sRNAs that are both SloR- and manganese-responsive. Taken together, this research can elucidate the details of regulatory networks that engage sRNAs in an important oral pathogen, and that can enable the development of an effective anti-caries therapeutic.

microbiology↗