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4. University of California, Los Angeles, Dr. Elizabeth Neufeld Update from the Laboratory of Dr. Elizabeth F. Neufeld, Department of Biological Chemistry at UCLA, November, 2009 Why is the brain so severely affected in patients with Sanfilippo Syndrome (MPS III)? To answer this question, we generated a mouse model of MPS IIIB ten years ago, with funding from The Children’s Medical Research Foundation and the National Institutes of Health We are beginning to see the answer. It is more complicated than we had anticipated, but may give us leads to better strategies to develop treatment. The primary defect in MPS III B is mutation in the gene, NAGLU, which leads to a deficiency of the enzyme alpha-N-acetylglucosaminidase and a storage of undigested heparan sulfate or its fragments in lysosomes. The original understanding was that the lysosomal storage interfered with the function of the cell by taking up a lot of space. However, that is not the case for the Sanfilippo Syndrome. The storage of heparan sulfate in liver lysosomes does not cause liver disease. But the storage of much smaller quantities of heparan sulfate in the brain causes very serious disease. This has led to a search for secondary defects in the brain. From data gathered several years ago, we had come to appreciate that many secondary accumulations, such as gangliosides, cholesterol, ubiquitin and other substances, occurred in a very small area of the mouse brain called the Medial Entorhinal Cortex (MEC). To see what was so unique about this area, we dissected neurons from the MEC of MPS IIIB mice and of unaffected control mice, as well as from a neighboring area (the Lateral Entorhinal Cortex or LEC) that does not show these secondary accumulations. Analyzing gene expression in these neurons gave us a lead about a protein, lysozyme, which was elevated in MEC neurons of the MPS IIIB mouse brains but not LEC neurons. Lysozyme (a protein associated with inflammation, which had not been previously reported in neurons) is a protein which is thought to aggregate very easily, and we postulated that lysozyme accumulated in neurons because it aggregated and then could not be broken down. There was a report in the literature that aggregated lysozyme was toxic to neurons and could lead to the accumulation of hyperphosphorylated tau (P-tau, a protein that accumulates in the brains of patients with Alzheimer’s disease). We therefore searched for the presence of P-tau in the MPS IIIB mouse brain. Indeed, we found P-tau in the MEC of MPS IIIB mice as well as in the dentate gyrus (an area to which MEC is connected). We also found an elevation in MEC of an activated form of the enzyme GSK3b, which is thought to be responsible for the formation of P-tau. GSK3b could be a target for therapy because there are many compounds that reduce its activity, the best known of which is lithium. We put some mice on a diet supplemented with lithium salts, but our pilot experiment did not show any improvement in the pathology. Perhaps we did not use a sufficient dose or start early enough; we will therefore repeat the study under somewhat different conditions. Finally, we have just obtained evidence for aggregates of Ab, another feature of Alzheimer’s disease in the MEC of MPS IIIB mice. Our current concept of the pathogenesis of MPS IIIB is that the MEC is an area of the brain in which certain proteins are prone to aggregate – lysozyme, P-tau and Ab. Whatever it is in the MEC environment that predisposes to this aggregation, it eventually must connect to the primary defect – an inability to break down heparan sulfate. We can see that there may be many ways to provide treatment, each with its own advantages and disadvantages. Clearly, gene therapy would be ideal, but it is not yet ready for human use, although clinical trials are appearing on the horizon. Enzyme replacement would also be good, provided there were methods for delivering enzyme across the blood-brain barrier. But, unfortunately, these therapeutic methods are not yet available. We can also focus on the secondary defects. These could be inhibitors of GSK3bor they could be compounds that interfere with protein aggregation. Because protein aggregation is thought to be linked to dementia, such drugs might improve the quality of life for patients and their families. Finally, if we understood what it is about the MEC area that facilitates the aggregation of proteins, we could target that aspect of the disease. Reference: Ohmi K, Kudo L, Ryazantsev S, Zhao HZ, Karsten SL, Neufeld EF: Sanfilippo syndrome type B, a lysosomal storage disease, is also a tauopathy. Proceedings of the National Academy of Science 106: 8332-8337, 2009.
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