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4. University of California, Los Angeles, Dr. Elizabeth Neufeld We have been studying a mouse model of Sanfilippo syndrome type III B in order to better understand the development of the disease, particularly in the brain. The mouse model was generated eight years ago (with the help of funding from the CMRF) by disrupting the gene encoding a-N-acetylglucosaminidase, one of the enzymes required to break down heparan sulfate in lysosomes. As a result, heparan sulfate accumulates in lysosomes of many organs. Last year we reported that some neurons which accumulated heparan sulfate in the brain also accumulated other substances, which were not biochemically related to heparan sulfate or to each other and did not require a-N-acetylglucosaminidase for degradation. These other substances included lipids (GM3 ganglioside and cholesterol) and proteins (ubiquitin and SCMAS). What role this secondary storage of apparently unrelated substances plays in the disease process is not known; furthermore, it is not unique to MPS III B but also occurs in other lysosomal storage diseases. We believe that the primary storage material (heparan sulfate in MPS III B) causes lysosomes to become large and numerous and to generate signals to which the neurons respond by storage of the other substances named above. This constellation of stored material occurs only in a limited number of neurons, which we dubbed "vulnerable". In order to learn what kind of signals are sent out by the vulnerable neurons, we are examining the expression of genes in these neurons from an MPS III B mouse brain compared to expression in similar neurons from normal mouse brain. We are also comparing them with neurons in an adjacent area that does not have such storage. Using the technique of "laser capture microdissection", we have teased out about 500 individual vulnerable neurons from the brain of the MPS III B mice and a similar number of neurons from the corresponding area in the brain of normal mice. That was sufficient to obtain gene transcripts (i.e., messenger RNAs) and determine the genes to which they correspond, using another state-of-the-art technology named "gene microarray". This work is only starting and to date we have performed one study to determine feasibility of the approach. There was interesting information even in this preliminary experiment, but we prefer to wait till we have confirmed it before describing it in this forum. We hope that this approach will lead to the discovery of unsuspected pathways, which contribute to the disease process and which may eventually be used as targets for pharmacological intervention.
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