Storage disorders as originally conceived were believed caused by an absence of hydrolytic enzyme activity within end-organelles (lysosomes) possessing numerous degradative enzymes in an acid milieu. Substrates requiring the missing enzyme for degradation accumulated within tertiary lysosomes and over time cytoplasmic crowding was believed to lead to compromise in cell function followed by cell death. Glycosphingolipids (GSLs), mucopolysaccharides and glycoproteins were documented as typical substrates requiring the lysosome for degradation and numerous classes of storage diseases were established on the basis of their accumulation (glycosphingolipidoses, mucopolysaccharidoses, glycoproteinoses, etc.). Many of these storage compounds were prominently expressed in brain where limited neurogenesis and the need for long-term neuronal survival were believed to amplify the cytotoxic effects of intracellular storage. Importantly, studies of recent years have significantly altered this view of lysosomal storage disorders. Firstly, proteins involved in a host of non-lysosomal and/or non-enzymatic functions have now been documented as causes of intracellular lysosomal storage. Some of these proteins are essential for processing or targeting of lysosomal enzymes but others are soluble non-enzyme lysosomal proteins or are transmembrane proteins involved in organelle or substrate trafficking. Secondly, the lysosome itself has come to be viewed not simply as an independent end-organelle, but rather as a cell component in dynamic continuum with endosomes. The endosomal-lysosomal system has itself been established as critical not only for the degradation and recycling of molecules but also in signal transduction events and homeostatic control mechanisms. Many of the molecules transiting through the endosomal-lysosomal system (GSLs, cholesterol, etc.) have been identified as constituent parts of specialized microdomains (""""""""rafts"""""""") believed to act as signaling platforms in the plasmalemma. Consequently, lysosomal storage diseases may represent states of disordered raft function with storage consisting of """"""""log jams"""""""" of rafts within endosomes and lysosomes. Such abnormalities are particularly relevant to storage in brain where neurons do not simply degenerate but undergo bizarre and unique alterations ranging from sprouting of new, synapse-covered ectopic dendrites on some classes of neurons to formation of unusual axonal abnormalities on others. The current proposal will use a combination of in vivo and in vitro analyses and murine models of neuronal storage diseases to test specific hypotheses focused on the molecular/cellular pathogenesis of storage diseases. Such advances in understanding we believe will provide new insights into potential treatment strategies and further elucidate the critical role played by the endosomal-lysosomal system in both health and disease. ? ?
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