Research by the Laser Analytics Group recently published in the Journal Neuron contributes major new insights into the molecular pathology of motor neurone disease (also called amyotrophic lateral sclerosis, or ALS) and related neurogenerative disesases such as Alzheimer’s and Parkinson’s.
In work published in the Journal Neuron we used a technique called single particle tracking and fluorescence lifetime imaging microscopy we were able to track the aggregation state of a protein called FUS inside cell models of disease. FUS is strongly associated with the pathology of motor neurone disease but appears to have an important function also in normal, healthy cells. Intriguingly our research, and that of others, show that the protein can form so called ‘hydrogels’, soft jelly like structures, that consist mostly of water, rather like the Jello Cubes shown in the picture above (image credit Steven Depolo).
These hydrogels seem to be made up of strings of FUS protein, daisy chained into structures that are called ‘protein amyloids’. Amyloids are aggregates of proteins that are most often associated with diseases such as Alzheimer’s and Parkinson’s. Usually amyloid formation is irreversible: Once a protein clumps into aggregates, this process is irreversible (leading for example to the formation of the tell tale plaques in brains suffering from Alzheimer’s disease). FUS seems to be an amyloid with an important difference: It is capable of forming amyloids reversibly inside cells, it’s akin to jello cubes turning back and forth between liquid and gel states, which occurs for example through a cycling of temperature.
In normal cells this reversible aggregation behavior of FUS may have important physiological functions: For example, the hydrogels formed when aggregated may act as a cargo vehicles to carry molecules throughout the cell. Once the cargo arrives at the correct location in the cell, the hydrogels dissolve, releasing their cargo.
In ALS linked mutations of of FUS we found that aggregates cannot be ‘undone’ so that FUS behaves more like classical amyloids as found for example in Alzheimer’s and Parkinson’s diseases and this in turn may elicit the toxic response in cells observed in ALS. We were able to show that the rheology of FUS gels changes markedly in certain mutational variants of the proteins, and that gel dissolution was impossible in the mutations of FUS that have in previous work been associated with ALS. This may mean that reversible gel formation is an essential feature for cellular housekeeping functions.
We used a technique called single molecule particle tracking to show that molecular transport through FUS gels is significantly affected in the ALS mutants of FUS. The technique is capable of tracking the position and motion of individual molecules through the gels to a few billionths of a metre and thus to quantify the ‘leakiness’ of the gels for a range of conditions. We used fluorescence lifetime imaging microscopy on the other hand to track the aggregation state of FUS directly in cell models of disease, using a sensor concept for amyloid aggregation developed in our group.
The research is part of a large collaboration of research groups from the medical, biological, and physical sciences, led by Prof. Peter St. George-Hyslop.
For more information on this research see the University Press Release.
See also
Relevant papers:
A FRET sensor for non-invasive imaging of amyloid formation in vivo
Group members involved: