Visualizing protein misfolding in brain ageing

Active: 2020.03.02 - 2021.09.30
UK SPINE Scientific Liaison: Monica Spisar

During age-associated disease, a protein which is usually monomeric enters a conformational state that allows it to self-associate into oligomers and fibrils, which eventually form large deposits seen in the human brain. Despite these large deposits being the major pathological hallmark in ageassociated neurological disease, data indicates that the  earlier soluble oligomers are the most toxic in cells; there, their detection via conventional biochemical methods suffers from lack of sensitivity, hindering the ability to detect, and intervene in, the process of age related protein misfolding.

With the advent of super-resolution microscopy, which can study endogenous proteins at the nanoscale, and single-molecule techniques, which can detect individual molecules one-by-one and are able to identify the rarest of species, technologies are now available to visualise protein misfolding in human biofluids. This research will apply these innovative technologies to identify oligomer-based biomarkers of aging and to elucidate the proteostasis network in the brain.

Three lines of interrogation will be followed in this research.

1. Apply new and highly sensitive technologies to understand age-related decline of protein homeostasis. Capture the key aggregate that causes neuronal death in age related diseases, the oligomer. Determine whether the ‘toxic’ intermediate species of α-synuclein aggregation is a biomarker for impaired proteostasis and, thus, aging, pathological aging and disease.
2. Test the latest aging paradigms to determine whether it is possible to utilise aged iPSC derived neurons as a tractable model to study protein homeostasis, and understand how aging is a risk factor for proteinopathies. Directly compare the cell models of aging with data from human postmortem brain to fully validate these models. Visualise the different species of misfolded protein in models of aging and the G51D mutation to elucidate how protein aggregation occurs, and in which human cell types, and how aging exacerbates this process.
3. Capture the proteostasis network in brain and iPSC cells in the presence of oligomer formation to identify transcriptomics changes that will highlight key genes, and proteins that may be targeted to modulate protein homeostasis in aging and disease.