Frost, D. | bioRxiv Science

bioRxiv2023

Downregulation of the silent potassium channel Kv8.1 increases ALS motor neuron vulnerability

The Kv8.1 potassium ion channel encoded by the KCNV1 gene is a "silent" subunit whose biological function is unknown. In ALS patient-derived motor neurons carrying SOD1(A4V) and C9orf72 mutations, its expression is highly reduced, yielding increased vulnerability to cell death without a change in motor neuronal firing. Our data suggests that Kv8.1 modulates Kv2 channel function to impact neuronal metabolism and lipid/protein transport pathways, but not excitability.

neuroscience↗

bioRxiv2021

A Multiparametric Activity Profiling Platform for Neuron Disease Phenotyping and Drug Screening

Patient stem cell-derived models enable imaging of complex disease phenotypes and the development of scalable drug discovery platforms. Current preclinical methods for assessing cellular activity do not, however, capture the full intricacies of disease-induced disturbances, and instead typically focus on a single parameter, which impairs both the understanding of disease and the discovery of effective therapeutics. Here, we describe a cloud-based image processing and analysis platform that captures the intricate activity profile revealed by GCaMP fluorescent recordings of intracellular calcium changes and enables discovery of molecules that correct 153 parameters that define the amyotrophic lateral sclerosis motor neuron disease phenotype. In a high-throughput screen we identified compounds that revert the multiparametric disease profile to that found in healthy cells, a novel and robust measure of therapeutic potential quite distinct from unidimensional screening. This platform can guide the development of therapeutics that counteract the multifaceted pathological features of diseased cellular activity.

neuroscience↗