Aging is the main known risk factor for sporadic forms of neurodegenerative diseases associated with aberrant protein aggregation such as Alzheimer’s disease and Parkinson’s disease. Still we do not understand how aging contributes to pathogenesis. Significantly, we discovered that part of the proteome aggregates in aged Caenorhabditis elegans (DOI: 10.1371/journal.pbio.1000450). These results have since been confirmed in other organisms including mammals. Therefore protein aggregation is not restricted to a disease context as previously assumed but rather a major problem that the organism is confronted with during normal aging.
This novel marker of aging gives us the unprecedented opportunity to discover unique endogenous mechanisms responsible for promoting a healthy proteome. In particular, we aim to understand how longevity-related pathways deal with protein aggregation. Another main aspect of our research is to characterize the similarities and differences between age-dependent protein aggregation and disease-associated protein aggregation. Most importantly we are exploring how age-dependent protein aggregation is linked to unhealthy aging and neurodegeneration.
The model organism of choice used in our lab is the 1mm-long nematode C. elegans. With a short lifespan and its relative simplicity, this organism is an ideal model for aging research. We use a combination of genetic, biochemical, proteomic, microfluidic and high-resolution imaging techniques to investigate protein aggregation in C. elegans.
Some recent highlights from our lab show how changes with age could contribute to pathogenesis in neurodegenerative diseases:
In Lechler et al. (DOI: 10.1016/j.celrep.2016.12.033 and 10.1080/19336896.2017.1356559), we demonstrate the inherent aggregation propensity of key stress granule proteins in aging C. elegans. Importantly, we found that animals with stress granule aggregates were less fit compared to those without aggregation. Significantly, we discovered that maintaining dynamic stress granule proteins was a priority in long-lived animals. Overall, these findings help explain why stress granule proteins are often found in pathological protein aggregates and emphasize their potential role in promoting neurodegeneration.
In Groh et al. (DOI: 10.3389/fnagi.2017.00138), we prove for the first time that minute amounts of age-dependent protein aggregates cross-seed amyloid-β aggregation found in Alzheimer’ disease. Specifically, aggregates formed during middle-age in C. elegans initiated early amyloid-β aggregation in vitro. Confirming the relevance for mammals, we obtained similar effects using aggregates from aged wild-type mouse brains. Promising results using C. elegans suggest that cross-seeding is also likely to happen in vivo. Thus this proof-of-concept study provides experimental evidence for a direct link between the molecular mechanisms of aging and pathogenesis.