Investigating mitochondrial dysfunction as an early pathogenic mechanism of primary tauopathies, using MAPT splicing mutation iPSC-organoids

Pathway Grant

Principal Investigator: Dr. Kathryn Bowles, University of Edinburgh

Tauopathies are brain diseases that change behaviour, communication and movement, and get worse with time. There are currently no treatments to slow or stop them, so time is of the essence to find new therapies. Sometimes, tauopathies can run in families. About 40% of those families have a small but specific change in a gene called “MAPT”, which stops it from working properly. These changes are known as mutations. Mutations in MAPT change how well neurons function, and eventually causes them to die.

We have found that MAPT mutations can change how well neurons are able to produce energy by damaging the batteries that power our cells. These batteries are called mitochondria. We want to understand how mitochondria change in neurons with a MAPT mutation compared to those without. To do this, we will use stem cells, which have been made from blood cells of MAPT mutation patients. Stem cells will be turned into “mini-brains,” which are similar to tiny pieces of human brain that let us study how neurons work. We will then use these mini-brains to look at how mitochondria number, shape, location and function change in neurons with MAPT mutations, compared to those without.

This work will give us new insight into the very early changes that happen in the brains of people as they start to develop tauopathy. If we can understand what those changes are, we will be able to develop new treatments that can stop them from happening, and ultimately stop people from developing FTD.