David Group

David Group
David Group

The ultimate goal of our laboratory is to discover mechanisms to promote healthy ageing and alleviate age-related diseases. We aim to understand the molecular basis of ageing by focusing on a pathological adaptation to ageing, namely protein aggregation. We and others have identified several hundred proteins that accumulate in aberrant clumps both inside and outside of cells in ageing organisms in the absence of disease processes.

Mainly, we work with Caenorhabditis elegans, a transparent nematode about 1 mm in length, which is an outstanding model for ageing research. Ageing is easily monitored in this simple organism which undergoes rapid ageing over the course of two weeks. Our research in C. elegans reveals that protein aggregates contribute to the decline in muscle function with age. Therefore, identifying ways to keep proteins in their correct shape will likely promote healthy ageing.

Recently, we developed a C. elegans model to study extracellular protein aggregation. Using this model, we are exploring new ways to maintain the quality of proteins outside the cell. Other important goals of the lab are to understand what makes certain tissues more vulnerable to protein aggregation and how to enhance stress resistance with age. Mechanisms and concepts identified in C. elegans could open up new avenues in the search for therapies to delay disabilities of ageing in humans.

Extracellular aggregates

Protein aggregates (magenta puncta) accumulate between tissues in the head of the worm.

Latest Publications

Gallotta I, Sandhu A, Peters M, Haslbeck M, Jung R, Agilkaya S, Blersch JL, Rödelsperger C, Röseler W, Huang C, Sommer RJ, David DC Signalling

In metazoans, the secreted proteome participates in intercellular signalling and innate immunity, and builds the extracellular matrix scaffold around cells. Compared with the relatively constant intracellular environment, conditions for proteins in the extracellular space are harsher, and low concentrations of ATP prevent the activity of intracellular components of the protein quality-control machinery. Until now, only a few bona fide extracellular chaperones and proteases have been shown to limit the aggregation of extracellular proteins. Here we performed a systematic analysis of the extracellular proteostasis network in Caenorhabditis elegans with an RNA interference screen that targets genes that encode the secreted proteome. We discovered 57 regulators of extracellular protein aggregation, including several proteins related to innate immunity. Because intracellular proteostasis is upregulated in response to pathogens, we investigated whether pathogens also stimulate extracellular proteostasis. Using a pore-forming toxin to mimic a pathogenic attack, we found that C. elegans responded by increasing the expression of components of extracellular proteostasis and by limiting aggregation of extracellular proteins. The activation of extracellular proteostasis was dependent on stress-activated MAP kinase signalling. Notably, the overexpression of components of extracellular proteostasis delayed ageing and rendered worms resistant to intoxication. We propose that enhanced extracellular proteostasis contributes to systemic host defence by maintaining a functional secreted proteome and avoiding proteotoxicity.

+view abstract Nature, PMID: 32641833 08 2020

Huang C, Wagner-Valladolid S, Stephens AD, Jung R, Poudel C, Sinnige T, Lechler MC, Schlörit N, Lu M, Laine RF, Michel CH, Vendruscolo M, Kaminski CF, Kaminski Schierle GS, David DC Signalling

Reduced protein homeostasis leading to increased protein instability is a common molecular feature of aging, but it remains unclear whether this is a cause or consequence of the aging process. In neurodegenerative diseases and other amyloidoses, specific proteins self-assemble into amyloid fibrils and accumulate as pathological aggregates in different tissues. More recently, widespread protein aggregation has been described during normal aging. Until now, an extensive characterization of the nature of age-dependent protein aggregation has been lacking. Here, we show that age-dependent aggregates are rapidly formed by newly synthesized proteins and have an amyloid-like structure resembling that of protein aggregates observed in disease. We then demonstrate that age-dependent protein aggregation accelerates the functional decline of different tissues in . Together, these findings imply that amyloid-like aggregates contribute to the aging process and therefore could be important targets for strategies designed to maintain physiological functions in the late stages of life.

+view abstract eLife, PMID: 31050339 03 05 2019

Groh N, Gallotta I, Lechler MC, Huang C, Jung R, David DC Signalling

In the last decades, the prevalence of neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD), has grown. These age-associated disorders are characterized by the appearance of protein aggregates with fibrillary structure in the brains of these patients. Exactly why normally soluble proteins undergo an aggregation process remains poorly understood. The discovery that protein aggregation is not limited to disease processes and instead part of the normal aging process enables the study of the molecular and cellular mechanisms that regulate protein aggregation, without using ectopically expressed human disease-associated proteins. Here we describe methodologies to examine inherent protein aggregation in Caenorhabditis elegans through complementary approaches. First, we examine how to grow large numbers of age-synchronized C. elegans to obtain aged animals and we present the biochemical procedures to isolate highly-insoluble-large aggregates. In combination with a targeted genetic knockdown, it is possible to dissect the role of a gene of interest in promoting or preventing age-dependent protein aggregation by using either a comprehensive analysis with quantitative mass spectrometry or a candidate-based analysis with antibodies. These findings are then confirmed by in vivo analysis with transgenic animals expressing fluorescent-tagged aggregation-prone proteins. These methods should help clarify why certain proteins are prone to aggregate with age and ultimately how to keep these proteins fully functional.

+view abstract Journal of visualized experiments : JoVE, PMID: 29286457 26 11 2017

Group Members

Della David

Group Leader

Joseph Chadwick

Research Assistant