Russell, K. A. | Search bioRxiv

bioRxiv2026

Intrathecal (G4C2)149 delivery in C9orf72-deficient mice yields mild motor dysfunction and ALS/FTD pathological hallmarks

A repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet existing mouse models incompletely engage spinal regions implicated in disease. Here, an adeno-associated virus encoding (G4C2)149 repeats was delivered via neonatal intrathecal injection, achieving widespread CNS expression with robust spinal cord targeting. This approach was applied to mice with graded loss of endogenous C9orf72 to interrogate both gain- and loss-of-function mechanisms. Longitudinal motor, behavioral, and pathological analyses revealed that repeat expression primarily drives mild, progressive muscle weakness, whereas coordination deficits were largely genotype dependent. Subtle gait abnormalities and hyperactivity were also observed. Within spinal motor regions, repeat-expressing mice exhibited dipeptide repeat protein accumulation, reduced NeuN-positive area, glial activation, and sparse phosphorylated TDP-43 pathology. Cross-domain correlations further linked repeat expression, spinal pathology, and motor dysfunction. Collectively, these findings establish that CNS-wide repeat expression combined with reduced C9orf72 produces a coherent, mild ALS/FTD model.

neuroscience↗

bioRxiv2020

The direct and indirect effects of environmental toxicants on the health of bumble bees and their microbiomes.

Bumble bees (Bombus spp.) are important and widespread insect pollinators, but the act of foraging on flowers can expose them to harmful pesticides and environmental chemicals such as oxidizers and heavy metals. How these compounds directly influence bee survival and indirectly affect bee health via the gut microbiome is largely unknown. As the toxins and toxicants in floral nectar and pollen take many forms, we explored the genomes of core bumblebee microbes (Using RAST) for their potential to detoxify cadmium, copper, selenium, the neonicotinoid pesticide imidacloprid, and hydrogen peroxide - which have all been identified in floral nectar and pollen. We then exposed Bombus impatiens workers to varying concentrations of these chemicals spiked into their diet and identified the direct effects on bee survival. Using field realistic doses, we further explored indirect effects on bee microbiomes. We found multiple genes in core gut microbes that have the potential to aid in detoxifying harmful chemicals. We also found that while the chemicals are largely toxic at levels within and above field-realistic concentrations, the field-realistic concentrations - except for imidacloprid - altered the composition of the bee microbiome, potentially causing gut dysbiosis. Overall, our study shows that environmental chemicals found in floral nectar and pollen can directly cause bee mortality, and at field-realistic levels, likely have indirect, deleterious effects on bee health via their influence on the bee microbiome.

ecology↗