Sleiman, M. | Search bioRxiv

bioRxiv2026

Comparative analysis of neuronal proteolytic pathways reveals neuron-specific and sub-compartmental-specific capacities with aging

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 cytosol 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 cytoplasmic as well as synaptic neuronal subcompartments, the cerebellar proteasomal activity decreased only in the cytoplasmic compartment with aging. In C. elegans, we detected a decrease of proteasomal activity in both cytoplasmic and synaptic compartments of neurons. Interestingly, we observed a dysregulation of macroautophagy in both neuronal subcompartments of the cortex and cerebellum in mice as well as in C. elegans neurons with aging. Thus, we uncovered neuron-specific and subcompartmental-specific proteolytic capacities with aging that could manifest in different neuronal vulnerabilities for proteotoxic challenges with aging.

biochemistry↗

bioRxiv2025

Impairment of neuronal activity occurs at the early stages of the aggregation cascade of Ab1-42 and mutant Tau

Alzheimers disease (AD) is a progressive neurodegenerative disease that is characterized by the accumulation of amyloid-{beta} (A{beta}) plaques and neurofibrillary Tau tangles, ultimately leading to brain atrophy and death. To elucidate the relationship between the aberrant folding and aggregation of A{beta} and mutant Tau and neuronal function, we monitored neuronal activity in C. elegans AD models across age. Our findings reveal that expression of both A{beta} and Tau lead to significant reductions in neuronal activity and function in young adult animals preceding the accumulation of amyloid aggregates. Notably, A{beta} expression and aggregation in muscle tissue produced comparable detrimental effects on neuronal activity as its expression in neurons, suggesting that proteotoxic stress in muscle can influence neuronal function. This may occur through the propagation of A{beta} from muscle to neurons or through retrograde signaling pathways. Further, our new sub-stoichiometrically labeled Tau strains highlight that TauP301L,V337M has a significant impact on neuronal activity throughout aging. These results enhance our understanding of the early functional effects of amyloid aggregation in Alzheimers disease.

neuroscience↗