Pathogenic cascades in lysosomal disease-Why so complex? J Inherit Metab Dis

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: 4.14). 02/2009; 32(2):181-9. DOI: 10.1007/s10545-008-1040-5
Source: PubMed

ABSTRACT 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.
    The International Journal of Biochemistry & Cell Biology 11/2014; 58. DOI:10.1016/j.biocel.2014.11.001 · 4.24 Impact Factor
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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.
    Gene 09/2014; 555(1). DOI:10.1016/j.gene.2014.09.054 · 2.08 Impact Factor
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    • "Generally these diseases are multisystemic, and clinical features of many LSDs include organomegaly, central nervous system dysfunction and coarse hair and faces. Most LSDs are characterized by their progressive course with high morbidity and increased mortality, although there are significant variations between different diseases, and even among patients with the same disease (Walkley 2009). Lysosomal enzymes are ubiquitously distributed, but substrate storage is usually restricted to cells, tissues and organs with higher substrate turnover. "
    Non-Viral Gene Therapy, 11/2011; , ISBN: 978-953-307-538-9
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