Porter, Morwenna Yvonne;
(2004)
Caenorhabditis elegans as a model for the neuronal ceroid lipofuscinoses.
Doctoral thesis (Ph.D.), University College London (United Kingdom).
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Abstract
The neuronal ceroid lipofuscinoses (Batten disease) are a group of inherited neurological disorders which predominantly affect children. They are characterized by the accumulation of autofluorescent storage material in lysosomes and occur with a frequency between 1 in 12 500 and 1 in 100 000 births. To date, six genes underlying different sub-types of the disease have been cloned and many studies in cell culture and mouse models performed. However the mechanism of disease pathogenesis remains poorly understood. The simple nematode worm, Caenorhabditis elegans, has a fully sequenced genome, completely mapped cell lineage and nervous system, is easy to maintain and manipulate, and is an organism about which much information, including the results of many genome wide studies, is available. It is thus a good model organism for the study of genes that underlie human neurological disorders. The aim of this work was to investigate whether C. elegans could be used as a model system for investigating the function of NCL genes and the pathological mechanisms that underlie disease manifestation. Homologues to PPT1 and CLN3 were identified in C. elegans and their expression confirmed. Mutation of PPT1 underlies the most severe NCL type, infantile NCL (INCL). Further analysis of CePPT-1 determined a high level of sequence and structural similarity to the human enzyme and demonstrated that it could perform the same catalytic reaction under the same conditions. Analysis of a ppt-1 null mutant (MN1) identified a phenotype of developmental delay, defective egg laying and grossly abnormal mitochondrial morphology. A homologue to the enzyme, acyl-protein thioesterase-1 was also identified (ATH-1) and expression confirmed. The role of PPT-1 in the cell and how this may relate to the pathogenesis of INCL and other NCL types is presented.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D. |
| Title: | Caenorhabditis elegans as a model for the neuronal ceroid lipofuscinoses |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. |
| Keywords: | (UMI)AAIU643858; Biological sciences; Batten disease |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10103429 |
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