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The molecular mechanisms of protein aggregation in a living organism
A wide variety of human diseases, including Alzheimer’s, Parkinson’s, Huntington’s, and diabetes type II, are associated with the deposition of insoluble protein aggregates containing amyloid fibrils. The conversion of monomeric protein into amyloid fibrils has been studied extensively in test tube reactions, but how protein aggregation takes place in living cells and organisms remains poorly understood. A key difference between in vitro and in vivo conditions is that cells and organisms have evolved intricate networks for protein quality control. These include molecular chaperones that aid correct protein folding, and degradation machineries that eliminate aberrant protein species. Furthermore, amyloid formation in a biological context is affected by the presence of other cellular components, including membranes. The presence of membranes promotes amyloid formation of several disease-associated proteins, and membranes are also thought to be targeted by pore-forming aggregate species leading to toxicity.
In our lab, we use the roundworm Caenorhabditis elegans as a model organism to study disease-related protein aggregation in vivo. C. elegans is relatively short-lived and optically transparent, allowing us to track the aggregation of fluorescently labelled proteins across its lifespan. Using a combination of different microscopy techniques, genetics, biochemistry, structural biology, and mathematical modelling, we aim to obtain a molecular and quantitative understanding of protein aggregation and its relation to disease.
Using fluorescence lifetime imaging (FLIM), amyloid formation can be visualised in living C. elegans. The formation of amyloid-like inclusions by YFP-tagged alpha-synuclein and polyglutamine (40 glutamines, Q40) is associated with a reduction in the fluorescence lifetime. Laine, Sinnige et al. (2019) ACS Chem Bio 14(7), 1628-1636.
For more information, please see the website of the Sinnige lab.
“Tessa Sinnige studies protein aggregation using C. elegans as a model organism.”