Protein Aggregation and Aging
Dr. Della David
Research Group Leader
Otfried-Müller-Str. 23
72076 Tübingen
 +49 7071 9254-150


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.

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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 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.

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.

Key Publications

Groh N, Bühler A, Huang C, Li KW, van Nierop P, Smit AB, Fändrich M, Baumann F, David DC. Age-Dependent Protein Aggregation Initiates Amyloid-β Aggregation. Front Aging Neurosci. 2017 May 17; 9:138. doi: 10.3389/fnagi.2017.00138
Lechler MC, Crawford ED, Groh N, Widmaier K, Jung R, Kirstein J, Trinidad JC, Burlingame AL, David DC. Reduced Insulin/IGF-1 Signaling Restores the Dynamic Properties of Key Stress Granule Proteins during Aging. Cell Rep. 2017 Jan 10; 18:454-467. doi: 10.1016/j.celrep.2016.12.033
Della C. David. Aging and the aggregating proteome. Frontiers in Genetics. 2012 Nov 30; 3 doi: 10.3389/fgene.2012.00247
David DC, Ollikainen N, Trinidad JC, Cary MP, Burlingame AL, Kenyon C. Widespread protein aggregation as an inherent part of aging in C. elegans. PLoS Biol. 2010 Aug 10; 8:e1000450. doi: 10.1371/journal.pbio.1000450
David DC, Hauptmann S, Scherping I, Schuessel K, Keil U, Rizzu P, Ravid R, Dröse S, Brandt U, Müller WE, Eckert A, Götz J. Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J Biol Chem. 2005 Jun 24; 280:23802-14.


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