PhD Candidate Cedars-Sinai Medical Center West Hollywood, CA, United States
Abstract: Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease resulting in paralysis and death three to five years after diagnosis. It is a late-onset disease that typically presents in older populations, usually between the ages of 51 and 66, with aging being its greatest risk factor. However, cell models do not fully recapitulate aged conditions and often require external stressors to display disease phenotype. Thus, it is crucial to understand the transcriptomic events that occur during aging in order to modulate these effects in cell models. We have previously shown that aging pathways are disrupted in ALS spinal cords and spinal motor neurons. However, the anatomical and cell-specific aging within the spinal cord and its contributions to ALS pathogenesis are still unclear. In this study, we have created a single-nuclei transcriptomic atlas of mouse spinal cords from wild type (WT) and ALS mice carrying the SOD1G93A transgene. We profiled WT mice from embryonic day 13.5 up to 800 days old, and we profiled the ALS littermates from the same life stages up until they reached their paralytic endpoint at 160 days old. Our findings allowed us to identify dynamic changes in the transcriptome of each cell type during ALS progression and aging. Construction of gene co-expression networks also allowed us to define cell-specific aging and their contribution to ALS. Further analysis of regulatory networks revealed transcription factors that may drive these aging and ALS processes. These insights provide a framework for further studying factors driving ALS disease progression and offer valuable targets for faithfully modeling aging in in vitro models, developing ALS therapies, and guiding comparative aging studies.
Funding Source: California Institute for Regenerative Medicine
