Research Group

Sara Mole Research Group

Genetics and biology of disease

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The lab is interested in disease caused by genetic changes, and how study of these mutations and their effects can reveal important and complex aspects of cell biology that may otherwise be beyond current appreciation. We are interested in neurodegenerative diseases in particular. The molecular basis for most late onset cases is unknown, however, a small % is genetic, often causing earlier onset, and some genes have been identified. Combinations of variations in these genes are likely to contribute to the later onset disease. Identifying and characterising the biology of all neurodegenerative genes will give invaluable information on pathways that lead to neurodegeneration. These pathways will provide new therapeutic targets to delay onset of neurodegeneration.

We have focused for many years on the molecular genetics and biology of the neuronal ceroid lipofuscinoses (NCL), or Batten disease (see NCL Resource web site). These are the most common neurodegenerative disorders of childhood. Children suffer from progressive blindness, seizures, and decreasing cognitive and motor abilities, leading to premature death. The disease is characterised by the early accumulation of autofluorescent material in the lysosomes of most cells, and the eventual death of cortical neurons. Since lipofuscin accumulates during the normal ageing process, understanding the molecular basis of NCL disease may shed light on the biology of late onset neurodegeneration and even ageing. We are also interested in Chediak-Higashi Syndrome, another severe lysosome storage disorder with immunological defects and neurodegeneration.

Our approach is to use molecular genetics to identify disease genes, and to use mammalian cell systems and a simple model system to extend our knowledge of the biology of these genes and to provide new therapeutic targets and a system for screening small molecules. We currently use Schizosaccharomyces pombe, a fission yeast that has many small vacuoles, like mammalian lysosomes. We have a particular interest in the function of conserved NCL proteins, and of those located upstream of the lysosome.

Identification of NCL genes

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Most NCLs are inherited in an autosomal recessive manner. A molecular genetic approach has identified many of the NCL genes, with eight human genes identified so far, and several additional genes identified in mouse models. We now concentrate on identifying the genes causing rare, variant or unusual types of NCLs, making increasing use new technologies . Since 2006, much of this work is being done collaboratively with the Rare NCL Gene Consortium. We are also interested in mutations that affect known NCL genes but cause atypical disease phenotypes. All NCL genetic data is deposited in the Mutation Database for the NCLs and associated pages.

Use of fission yeast as a model system for disease

Yeast is a great model system for studying the basic biology of conserved disease genes because it is a unicellular organism with around 5000 genes and is genetically tractable. For our work studying diseases that affect the lysosome, the fission yeast Schizosaccharomyces pombe is ideal because this rod-shaped yeast has many small vacuoles (equivalent to mammalian lysosomes). We study the effect on cells of deleting or overexpressing human disease genes, and of mimicking disease-causing or targeted mutations. We also identify and investigate genes that interact genetically with the disease gene to identify the biological pathways in which the disease gene functions, since these may lead to the development of new therapies. We take our results using yeast to ask informed questions in mammalian cells, to further understand the biology of the proteins that cause disease, and their relevance to neuronal cell death.

 

So far, most work has used btn1, the yeast orthologue of the NCL gene CLN3, and this approach has revealed several novel aspects of Btn1, and therefore, CLN3 function. As well as affecting vacuole homeostasis, Btn1 also affects other independent pathways, and disease-causing missense mutations in Btn1 differentially affect these pathways, providing an explanation for variation in disease phenotype. One of our most significant recent findings is that Btn1 is a Golgi protein, and its deletion affects the morphology of these organelles. There are many trafficking pathways from the Golgi, so this explains why so many phenotypes occur when the yeast gene is deleted. This work led us to reconsider juvenile CLN3 disease, and we showed that the mutation found in most patients world-wide does not completely abolish CLN3 function. Other mutations in CLN3 may therefore cause different diseases.

 

We also use yeast to study lvs1, the homologue of the Chediak-Higashi Syndrome (CHS) gene. When lvs1 is deleted the yeast vacuoles are very large.

 

Additional

Links:

NCL Resource web site http://www.ucl.ac.uk/ncl/

MCL Mutation Database http://www.ucl.ac.uk/ncl/mutation.shtml

Rare NCL Gene Consortium http://www.ucl.ac.uk/ncl/RNGC.shtml

Books:

The Neuronal Ceroid Lipofuscinoses (Batten Disease) - edited by H.H. Goebel, S.E. Mole and B.D. Lake. 1999. IOS Press

The Neuronal Ceroid Lipofuscinoses (Batten Disease) - 2nd edition , edited by S.E. Mole, R. E Williams and H.H. Goebel, 2012. OUP Press

Journal issues:

Molecular basis of NCL - edited by S.E. Mole, A. Jalanko and G. Dawson

Biochim Biophys Acta - Molecular Basis of Disease Special Issue - 1762 (10): 849-954. 2006

Recent advances in the neuronal ceroid lipofuscinoses - edited by H.M. Mitchison and S.E. Mole

Eur J Paed Neurol - Supplement - 5 (Suppl A): 1-217. 2001