How faulty waste disposal proteins could lead to tau tangles in Alzheimer’s and FTD
Prof Selina Wray
University College London
1 September 2022 - 31 August 2023
Full project name:
The E3 ubiquitin ligase CHIP: a key regulator of tau proteostasis in human neurons
Researchers at University College London are investigating how a specific protein in the cell’s waste disposal system affects tau aggregation in human nerve cells.
Alzheimer’s disease and frontotemporal dementia (FTD) involve a build-up of toxic proteins in the brain. One of these proteins is tau, which forms tau ‘tangles’ inside nerve cells. This process contributes to nerve cell damage and cell death, resulting in cognitive decline symptoms of dementia. Although researchers have known about tau tangles in Alzheimer’s and FTD for a long time, how they begin to form is still unclear.
Recent evidence suggests that the cell’s waste disposal system may be faulty in diseases like Alzheimer’s and FTD. To investigate this further, Prof Selina Wray will study a single component of the cell’s waste disposal system, called CHIP. Previous research in mice indicate that CHIP may be important for sorting harmful tau proteins from healthy tau proteins, and clearing harmful tau from brain cells. However, research using human disease models is needed to confirm this.
What will they do?
Prof Selina Wray and her team at UCL will use stem cells to create human nerve cells in the lab. They will create nerve cells both with and without CHIP protein. They will then grow the cells and see whether cells without CHIP are more prone to tau tangles forming. Prof Wray’s team will also study whether tau proteins in cells without CHIP are different to tau in normal cells. The group will analyse the wider effects of getting rid of the CHIP protein to see whether this may encourage tau tangles to form.
The findings from Prof Wray’s Pilot Project will be an important way to understand how tau tangles form in people with Alzheimer’s or FTD. Evidence suggests the earliest molecular processes behind these diseases can start 15-20 years before symptoms show. Therefore, research that sheds light into how the disease process begins is critical for creating early intervention strategies, for example treatments and diagnostics targeting the early stages of disease.
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