A region-delineated snRNA-seq atlas of mouse spinal cord across lifespan resolves the interaction of normative aging programs with SOD1-G93A ALS.
Publication Year:
2026
PubMed ID:
41993486
Funding Grants:
Public Summary:
Getting older is the biggest risk factor for developing ALS, but scientists have never fully understood exactly how the normal aging process interacts with the disease. To figure this out, researchers created a highly detailed, lifelong map of the spinal cord, comparing the individual cells of healthy mice to those with an ALS-like condition. They discovered that different sections of the spinal cord react to the disease differently, which explains why the lower spine tends to break down much faster than the neck area. Long before any physical symptoms even started, researchers noticed that the natural "waste disposal" system inside the cells of those vulnerable areas had already begun to fail. Interestingly, they also found that having ALS doesn't just cause the entire spinal cord to age faster. Instead, only the nervous system's dedicated immune cells showed signs of rapid, unnatural aging. Ultimately, this comprehensive lifelong map helps explain exactly how the normal aging process collides with hidden cellular damage to trigger the devastating effects of ALS.
Scientific Abstract:
Aging is the strongest risk factor for amyotrophic lateral sclerosis (ALS), yet how normative aging programs intersect with disease mechanisms remain unclear. Here we generated a lifespan-resolved, cell type- and region-specific single-nucleus RNA-sequencing atlas of the mouse spinal cord spanning embryonic development through advanced age in WT mice and end-stage disease in the SOD1-G93A ALS model. This resource enabled systematic comparison of physiological aging trajectories with disease-associated transcriptional changes across spinal cord cell types and rostrocaudal regions. We found that SOD1-G93A transcript and protein states differed markedly across spinal regions during disease onset and progression, and these molecular patterns paralleled the relative resilience of cervical regions and the heightened vulnerability of lumbar regions to degeneration in this transgenic mouse model. Prior to disease onset, we identified reduced ubiquitin expression that primed region-specific disruption of proteostasis in the SOD1-G93A spinal cord. Despite these disease-associated changes, aging-related transcriptional programs were largely preserved across most cell types, arguing against a global acceleration of aging in ALS. Instead, microglia emerged as a key exception, exhibiting accelerated and rewired aging- and disease-associated gene expression modules regulated by MITF and NRF2. Together, these findings provide an anatomically, cellularly, and temporally resolved framework for understanding how aging programs interact with disease-specific pathways to shape regional dysfunction and neurodegeneration in ALS.