Comparative analysis of neuronal proteolytic pathways reveals neuron-specific and sub-compartmental-specific...

Proteostasis is essential for maintaining neuronal function, and its dysregulation is a hallmark of aging and neurodegeneration. The ubiquitin-proteasome system (UPS) and macroautophagy are the two major proteolytic pathways responsible for protein degradation. However, their capacity and regulation differ between cell types and across aging. To elucidate the activity of both proteolytic pathways with aging, we performed a comparative analysis of the activity of UPS and macroautophagy in distinct neuronal subcellular compartments, in the soma and at synaptic terminals, across aging in neurons of Mus musculus (mouse) and Caenorhabditis elegans (nematode). In mice, our results identified differences between brain areas. While the cortical proteasomal activity declined with aging in both the somatic as well as synaptic-enriched neuronal subcompartments, the cerebellar proteasomal activity decreased only in the somatic-enriched compartments with aging. In C. elegans, we detected a decrease of proteasomal activity in both somatic and synaptic compartments of neurons. Interestingly, we observed an age-dependent change in several markers of autophagy in different fractions and brain areas of mice and a reduction of autophagosomes and autolysosomes with aging in C. elegans. Thus, we uncovered neuron-specific and subcompartmental-specific proteolytic capacities with aging that could manifest in different neuronal vulnerabilities for proteotoxic challenges with aging.