What are the consequences of endosomal disruption in neurons?

Lead researcher: Dr Sean Sweeney, Department of Biology

Dr Sweeney's group studies the cellular mechanisms driving frontotemporal dementia (FTD) progression, a common early onset dementia that can often run in families.

They use the advanced genetics of fruit flies to identify molecules and mechanisms causing disease pathology, and then progress to mammalian neurons to confirm these mechanisms.

His group has identified a pro-apoptotic signal activated by a genetic form of FTD that appears to be active more broadly in other forms of FTD and amyotrophic lateral sclerosis – a disease that can exist in a genetic spectrum with FTD.

From this, the group has identified an FDA-approved drug that can reverse many of the aspects of neuronal death and atrophy that are observed in fruit flies and mammalian neurons.

The group is currently investigating the mechanism of this drug with a longer term drive to use this in patient therapy.

This research is funded by the Medical Research Council, Alzheimer’s Society, Alzheimer’s Research UK, Orphan Disease Network, Motor Neurone Disease Association and the Biotechnology and Biological Sciences Research Council.

References

1. West, R.J.H., Ugbode, C., Gao, F.-B. and Sweeney, S.T. (2018) The Pro-Apoptotic JNK Scaffold Protein POSH/SH3RF1 Mediates Toxicity in CHMP2BIntron5-Associated Frontotemporal Dementia. Human Molecular Genetics, 27: 1382-1395
2. West, R.J., Lu, Y., Marie, B., Gao, F.B. and Sweeney, S.T. (2015) Rab8, POSH and TAK1 Regulate Synaptic Growth in A Drosophila Model of Frontotemporal Dementia J. Cell Biology. 208: 931-47