Longitudinal single-cell transcriptional profiling identifies dynamic neurodegenerative mechanisms in Christianson Syndrome rat

Endolysosomal dysfunction is a key element in numerous neurodegenerative disorders. Christianson syndrome (CS), an early-onset neurodegenerative disease, is caused by loss-of-function mutations in the endosomal Na+/H+ exchanger NHE6, leading to lysosomal dysfunction. While CS shares pathological similarities with more prevalent neurodegenerative diseases, the extent of mechanistic overlap is not fully understood.

Utilizing single-nucleus RNA sequencing throughout the lifespan of a CS rat model, researchers have delineated the temporal progression of disease at the single-cell level within the hippocampus.

Initially, neurons display transcriptional signatures indicative of mitochondrial dysfunction. In vitro and ex vivo investigations of mitochondrial function reveal progressive defects in quality control and bioenergetics within NHE6-null tissue. Moreover, transcriptomic and proteomic analyses uncover a comprehensive activation of innate immunity, specifically the cGAS-STING signaling pathway, which localizes to microglia.

Consequently, in the CS rat brain, early neuronal endosomal and mitochondrial impairments give way to significant microglial and astrocytic activation, alongside age-related declines in oligodendrocyte myelinating capacity.

Comparing cross species findings between the CS rat and human postmortem Alzheimer's disease hippocampus, researchers discover a substantial overlap in single-cell analyses. In summary, these findings elucidate the cellular trajectories of neurodegeneration in CS and identify common endolysosomal, mitochondrial, and inflammatory mechanisms that could potentially broaden the understanding of Alzheimer's disease pathogenesis.