Using forebrain organoids carrying FTD-causing MAPT mutations, we previously demonstrated that increased expression of the RNA binding protein ELAVL4 lead to alterations in glutamate synaptic signaling, making neurons more susceptible to death. Following on from this work, we are now investigating the mechanism by which ELAVL4 and mutant tau interact to disrupt the synapse, and whether we can reverse this process in order to protect neurons.
MAPT expression is highest in neurons, but it is present at very low level in astrocytes. Furthermore, many primary tauopathies are characterised by the accumulation of tau in astrocytes. This project aims to investigate the effect that MAPT expression and accumulation in astrocytes has both on the astrocytes themselves (cell autonomous effects) and on surrounding neurons (non-cell autonomous effects).
The expression of 4R tau is crucial to adult human brain function, but this isoform specifically accumulates in several primary tauopathies, such as PSP. However, iPSC-neurons typically do not express much 4R tau, so it has been challenging to investigate the role of this isoform in these models. We have generated a unique set of isogenic iPSC lines with MAPT mutations that cause high levels of 4R tau in iPSC-neurons, and we are now characterising the effect of these mutations in 2D and 3D culture models, and in human brain.
We have previously found that higher LRRC37A2 expression may be protective against risk for Parkinson's, but we don't know why. It is an interesting gene in the 17q21.31 "MAPT" locus with multiple copy number variants that has not been previously studied. We are using iPSC models to try to understand what the function of LRRC37A2 is in astrocytes, and how increasing its expression may protect neurons.
The inversion at the 17q21.31 locus covers around 1Mb of DNA, and is genetically associated with over 100 different clinical human traits, including several neurodegenerative diseases. Suprisingly, very little is known about the functional differences between the H1 and H2 haplotypes, and why one haplotype should increase risk for disease and the other is protective. We are collaborating with the Goate (MSSM), Geschwind (UCLA) and Kampmann (UCSF) labs to understand the differential regulatory elements and functional consequences of the inversion across different neural cell types.