Nicotinic acetylcholine receptors mediate fast synaptic transmission in the central nervous system, peripheral ganglia and at neuromuscular junctions.  Their role in genetic and autoimmune disorders is well established, as is their   use as potential targets for new drugs to treat the symptoms of Alzheimer’s disease and Parkinson’s disease, as well as conditions like nicotine addiction.

My laboratory has two main research goals: (a) to identify the diverse functions of nicotinic acetylcholine receptors and to determine their roles in nervous system and neuromuscular diseases and as drug/chemical targets; (b) to generate and study invertebrate models (the nematode worm, Caenorhabditis elegans and the fruitfly, Drosophila melanogaster) of human neurodegenerative diseases such as Alzheimer’s Disease (AD).  To achieve these goals we use the following techniques: electrophysiology, calcium imaging, genomics, genetics, computational modelling and, most recently, proteomics.

Current Research Programme

Nicotinic acetylcholine receptors (nAChRs) are membrane proteins, each molecule containing five subunits.  Advances in genomics have shown that large gene families encode nAChR subunits.  The diverse physiology and pharmacology of the approximately 30 human nAChR subtypes are determined in large part by differences in their subunit composition.  The roles of nAChRs in genetic disorders (congenital myasthenia syndrome (CMS) and some epilepsies), autoimmune disorders (e.g. myasthenia gravis) are increasingly well understood.  The potential of nAChRs as targets for novel drugs being developed to ameliorate the symptoms of Alzheimer’s disease, Parkinson’s disease, as well as tackling nicotine addiction and pain control is of considerable interest.  Our studies focus mainly on human, nematode (C. elegans) and fruitfly (D. melanogaster) nAChRs, although findings from other recently completed genomes have also proved instructive.

Recently, we have demonstrated differential actions on the three major nAChR subtypes (a7, a4b2, a3b4) of the b-amyloid peptide Ab1-42, which plays a key role in sporadic Alzheimer’s disease.  We are also testing on the same three nAChR subtypes the actions of Ab-amyloid peptide mutations that account for the familial (Swedish, Dutch and Flemish) forms of Alzheimer’s disease. 

In collaboration with colleagues at The Weatherall Institute of Molecular Medicine (Oxford University) and Oxford Brookes University, we have shown that autoantibodies to nAChR a7 subunits are present in some patients with Rasmussen’s encephalitis, thereby demonstrating a new mechanism for this disorder, with important implications for patient management.  With Dr Bethan Lang (Weatherall Institute of Molecular Medicine), we plan to screen sera from other patient groups to discover if other important disorders can be linked to nAChR autoantibodies.

The nematode worm C. elegans was the first animal with a nervous system to have its genome sequenced and, with only 302 neurons, approximately 5000 synapses and its cell lineage complete, it provides an ideal model for addressing fundamental questions in neuroscience.  Our studies on worm nAChRs and associated proteins, using forward and reverse genetics, have permitted the identification of major antiparasitic drug targets.   Our work on fly and related insect nAChR families has shown for the first time that pre-mRNA A-to-I editing adds considerably to nAChR subunit diversity and such editing can generate diversity in otherwise highly conserved regions such as the ACh binding site.

These discoveries on RNA editing may also have implications for human motor neuron disorders such as amyotrophic lateral sclerosis (ALS), where under-editing of ligand-gated ion channels has been demonstrated.  The roles of individual Drosophila nAChR subunits in cholinergic neurons are being addressed using a combination of RNAi, microarrays and physiology. 

Computational modelling of drug–nAChR interactions is underway in collaboration with Mark Sansom and Phil Biggin (Biochemistry, Oxford). Thus genomics, forward and reverse genetics, physiology, microarrays and computational modelling are enhancing our understanding of the functions of nAChRs, their roles in disease and as drug/chemical targets.

We have also developed and characterised C. elegans models for CMS and spinal muscular atrophy (SMA); we are exploring these models to gain insights into disease mechanisms and as vehicles for in vivo drug screening.  A fly model of AD is being studied in collaboration with colleagues in Cambridge and we have generated a new transgenic fly in which Ab1-42 is expressed only in cholinergic neurons.  New worm models of AD will be generated and studied.  Such invertebrate models offer advantages of speed, ease of manipulation and investigation.  Their power lies in the rapid development and testing of new hypotheses relating to disease mechanisms and the exploration of new routes to therapy for nervous system and neuromuscular disorders.   

Further information can be found at: http://www.mrcfgu.ox.ac.uk/research/david-sattelle

David Sattelle