Lysosomal disease represents a complex family of nearly 60 disorders linked by inherited defects in specific proteins critical for lysosomal function. At least two-thirds have significant impact on brain function, causing mental retardation, dementia, severe motor and sensory impairments, psychosis and behavioral changes, and seizures. Most lysosomal diseases have onset in infancy or childhood and dramatically compromise and shorten the lives of affected individuals. Few effective treatments, other than symptomatic, are available. The complex spectrum of neurological symptoms exhibited by individuals with lysosomal disease is reflected in a similar diversity of underlying molecular and cellular abnormalities. In addition to lysosomal storage, these include extopic dendritogenesis and altered synapse formation, axonal spheroid formation and selective neuronal degeneration. It is increasingly recognized that lysosomal diseases also exhibit alterations in autophagy as well as abnormal protein aggregation suggesting involvement of chaperone-mediated autophagy (CMA) and the ubiquitin proteosomal system (UPS). Such findings point to the presence of pathogenic cascades in lysosomal disease that resemble those in commoner forms of neurodegeneration, including Alzheimer's and Parkingson's diseases. Importantly, new evidence also indicates that lysosomal diseases aren't simply states of overabundance or storage, but also """"""""states of deficiency"""""""" in that lack of salvage products from lysisimal processing may deprive cells of key metabolites. As naturally occurring states of """"""""starvation-induced stress"""""""", neurons in lysosomal disease may be undergoing chronically induced autophagy as well as upregulation of synthetic pathways to replenish unavailable metabolites. Such changes could have profound effects on neurons over time and may be causally linked to formation of axonal spheroids and ectopic dendrites. In order to understand these complex events which we believe will provide new insights for therapy development, we have emphasized the need to """"""""think outside the organelle"""""""" - that is, to view lysosomal function from the view of """"""""streams"""""""" involving endosomal, autophagosomal and salvage systems. Thus we have proposed that the lysosomal system is not simply a degradative site, but rather is a central metabolic coordinator that can exert significant influence over nearly every aspect of the life of the cell, from signal transduction (via endocytosis) to metabolic homeostatic regulation (via autophagy and salvage).
Lysosomal Disease represents a complex family of nearly 60 disorders caused by inherited defects in specific proteins that are integral to lysosomal function. While individually rare, lysosomal disease as a whole affects individuals with an estimated incidence of 1:7500 live births, making these disorders intermediate between well known genetic conditions such as cystic fibrosis and phenylketonuria. Most lysosomal disorders have onset in infancy or childhood and cause death sometimes after years, or decades, of declining health. Few therapies, other than symptomatic ones, presently exist. These diseases affect many tissues and organs, including bone and connective tissue, heart and skeletal muscle, the immune system, and liver and other viscera. The brain is affected in at least two-thirds of these disorders, causing mental retardation, dementia, motor and sensory dysfunction, psychosis, and seizures. Lysosomal disease thus represents a significant burden on affected individuals, their families, the health care system and Society at large. In spite of major advances in identifying defective genes and proteins responsible for lysosomal disease, pathogenic mechanisms remain poorly understood. Yet it is now widely recognized that understanding pathogenesis of complex genetic diseases is critical to effectively developing new treatments. The current proposal is focused on the goal of fully understanding the critical role played by the lysosome and its related cellular components - the greater lysosomal system - by relating specific abnormalities found in these diseases to defects in the relationship between lysosomes and endocytosis, autophagocytosis, and salvage mechanisms. Insights derived from these studies will not only aid in therapy development for lysosomal disease, but may also provide insight into commoner forms of neurodegenerative disease, including Alzheimer's.
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