Prof R Wayne Davies

Molecular mechanisms of nerve cell death - focus on Parkinson's Disease

The research of this laboratory concerns genetic and molecular analysis of how particular nerve cells die. Our focus is on Parkinson's Disease and related human diseases, the central feature of which is malfunction and death of particular nerve cells, which make the neurotransmitter dopamine. When these cells die, lower amounts of the transmitter dopamine are delivered to a part of the brain (the caudate-putamen) which plays a key role in the control of movement, leading to the well-known symptoms of Parkinson's Disease. It is likely that Parkinson's Disease, and related disease such as Multiple System Atrophy and Dementia with Lewy Bodies, have both environmental and genetic causes. Nerve cells that make dopamine are particularly sensitive to certain chemical toxins, which affect the electron transport chain in mitochondria - such as MPP+ and rotenone. Human genetics has shown that mutations in several different genes can lead to hereditary parkinsonism; most well characterised are defects in the ubiquitin/proteasome garbage disposal pathway, and in a nerve terminal protein called alpha synuclein.

This laboratory is taking two approaches to shed further light on the molecular events that happen when these nerve cells are triggered to die. We are focusing particularly on a new candidate pathway that has been discovered by work of this laboratory and our collaborators, Dr RG Sutcliffe and Professor A.P.Payne. This is the nerve cell death pathway initiated by mutation in the agu gene, which we have recently identified by positional cloning. The protein altered by this mutation is a protein kinase that is centrally involved in cell signalling pathways, and offers an exciting opportunity to learn more about how these nerve cells can be triggered to die. One research direction is molecular and biochemical analysis of the affected pathway(s) in nerve cells that make dopamine, and other nerve cells. Also, together with colleagues expert in the system, we are initiating research with the fruit fly system in order to take a genetic approach to dissecting this pathway of nerve cell death.