Walkley, SU. Pathogenic cascades in lysosomal disease-Why so complex? J Inherit Metab Dis 32: 181-189

Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Center, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, NY, 10461, USA.
Journal of Inherited Metabolic Disease (Impact Factor: 3.37). 02/2009; 32(2):181-9. DOI: 10.1007/s10545-008-1040-5
Source: PubMed


Lysosomal disease represents a large group of more than 50 clinically recognized conditions resulting from inborn errors of metabolism affecting the organelle known as the lysosome. The lysosome is an integral part of the larger endosomal/lysosomal system, and is closely allied with the ubiquitin-proteosomal and autophagosomal systems, which together comprise essential cell machinery for substrate degradation and recycling, homeostatic control, and signalling. More than two-thirds of lysosomal diseases affect the brain, with neurons appearing particularly vulnerable to lysosomal compromise and showing diverse consequences ranging from specific axonal and dendritic abnormalities to neuron death. While failure of lysosomal function characteristically leads to lysosomal storage, new studies argue that lysosomal diseases may also be appropriately viewed as 'states of deficiency' rather than simply overabundance (storage). Interference with signalling events and salvage processing normally controlled by the endosomal/lysosomal system may represent key mechanisms accounting for the inherent complexity of lysosomal disorders. Analysis of lysosomal disease pathogenesis provides a unique window through which to observe the importance of the greater lysosomal system for normal cell health.

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    • "and ␤-hexosaminidase (Hex, EC activity, respectively, characterized by prominent nervous system degeneration involving disruption of the internal environment of the lysosome (Mahuran, 1999; Walkley, 2009). Hex is an acidic glycohydrolase that cleaves terminal ␤linked N-acetylglucosamine or N-acetylgalactosamine residues from oligosaccharides, glycolipids, glycoproteins and glycosaminoglycans (Mahuran, 1999) while Gal catalyses the hydrolysis of terminal N-linked galactosyl moiety from oligosaccharides and glycosides (Okada and O'Brien, 1968). "
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    ABSTRACT: A critical role of endosomal-lysosomal system alteration in neurodegeneration is supported by several studies. Dysfunction of the lysosomal compartment is a common feature also in Alzheimer’s disease. Altered expression of lysosomal glycohydrolases has been demonstrated not only in the brain and peripheral tissues of Alzheimer’s disease patients, but also in presymptomatic subjects before degenerative phenomenon becomes evident. Moreover, the presence of glycohydrolases associated to the plasma membrane have been widely demonstrated and their alteration in pathological conditions has been documented. In particular, lipid microdomains-associated glycohydrolases can be functional to the maintenance of the proper glycosphingolipids pattern, especially at cell surface level, where they are crucial for the function of cell types such as neurons. In this study we investigated the localization of β-hexosaminidase and β-galactosidase glycohydrolases, both involved in step by step degradation of the GM1 to GM3 gangliosides, in lipid microdomains from the cortex of both an early and advanced TgCRND8 mouse model of Alzheimer’s disease. Throughout immunoprecipitation experiments of purified cortical lipid microdomains, we demonstrated for the first time that β-hexosaminidase and β-galactosidase are associated with post-synaptic vesicles and that their activities are increased at both the early and the advanced stage of Alzheimer’s disease. The early increase of lipid microdomain-associated β-hexosaminidase and β-galactosidase activities could have relevant implications for the pathophysiology of the disease since their possible pharmacological manipulation could shed light on new reliable targets and biological markers of Alzheimer’s disease.
    Full-text · Article · Nov 2014 · The International Journal of Biochemistry & Cell Biology
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    • "Coutinho et al. / Gene xxx (2014) xxx–xxx Please cite this article as: Coutinho, M.F., et al., From bedside to cell biology: A century of history on lysosomal dysfunction, Gene (2014), http:// Apart from these central cellular functions, lysosomes can also be implied in processes such as cholesterol homeostasis, cell membrane repair (calcium regulated), fertilization, receptor recycling and regulation, cell division, skin pigmentation as well as in bone and tissue remodeling (Vellodi, 2005; Saftig, 2006; Walkley, 2009; Parkinson-Lawrence et al., 2010; Boustany, 2013). As a whole, the lysosomal system functions as a highly efficient and coordinated network essential for the metabolic homeostasis of the cell. "
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    ABSTRACT: Lysosomal storage disorders (LSDs) are a group of rare genetic diseases, generally caused by a deficiency of specific lysosomal enzymes, which results in abnormal accumulation of undegraded substrates. The first clinical reports describing what were later shown to be LSDs were published more than a hundred years ago. In general, the history and pathophysiology of LSDs have impacted on our current knowledge of lysosomal biology. Classically, depending on the nature of the substrates, LSDs can be divided into different subgroups. The mucopolysaccharidoses (MPSs) are those caused by impaired degradation of glycosaminoglycans (GAGs). Amongst LSDs, the MPSs are a major group of pathologies with crucial historical relevance, since their study has revealed important biological pathways and highlighted interconnecting pathological cascades which are still being unveiled nowadays. Here we review the major historical discoveries in the field of LSDs and their impact on basic cellular knowledge and practical applications. Attention will be focused on the MPSs, with occasional references to other LSDs. We will show as studies on the metabolic basis of this group of diseases have increased our knowledge of the complex degradative pathways associated with the lysosome and established the basis to the development of specific therapeutic approaches aiming at correcting or, at least ameliorating their associated phenotypes.
    Full-text · Article · Sep 2014 · Gene
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    • "In lysosome storage disorders (LSDs), several pathogenic cascades have been described secondary to the substrate accumulation in the lysosomal-endosomal system.38,61,62 These cascades include calcium signaling, altered lipid trafficking, oxidative stress, ER stress/unfolded protein response, autophagy, and inflammation.38 "
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    ABSTRACT: Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal disorder caused by the deficiency of arylsulfatase A (ASA), resulting in impaired degradation of sulfatide, an essential sphingolipid of myelin. The clinical manifestations of MLD are characterized by progressive demyelination and subsequent neurological symptoms resulting in severe debilitation. The availability of therapeutic options for treating MLD is limited but expanding with a number of early stage clinical trials already in progress. In the development of therapeutic approaches for MLD, scientists have been facing a number of challenges including blood-brain barrier (BBB) penetration, safety issues concerning therapies targeting the central nervous system, uncertainty regarding the ideal timing for intervention in the disease course, and the lack of more in-depth understanding of the molecular pathogenesis of MLD. Here, we discuss the current status of the different approaches to developing therapies for MLD. Hematopoietic stem cell transplantation has been used to treat MLD patients, utilizing both umbilical cord blood and bone marrow sources. Intrathecal enzyme replacement therapy and gene therapies, administered locally into the brain or by generating genetically modified hematopoietic stem cells, are emerging as novel strategies. In pre-clinical studies, different cell delivery systems including microencapsulated cells or selectively neural cells have shown encouraging results. Small molecules that are more likely to cross the BBB can be used as enzyme enhancers of diverse ASA mutants, either as pharmacological chaperones, or proteostasis regulators. Specific small molecules may also be used to reduce the biosynthesis of sulfatides, or target different affected downstream pathways secondary to the primary ASA deficiency. Given the progressive neurodegenerative aspects of MLD, also seen in other lysosomal diseases, current and future therapeutic strategies will be complementary, whether used in combination or separately at specific stages of the disease course, to produce better outcomes for patients afflicted with this devastating inherited disorder.
    Full-text · Article · Aug 2013 · Drug Design, Development and Therapy
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