Lysosomal dysfunction

Raben N, HiU V, Shea L, Takikita S, Baum R, et al. (2(X)8) Suppression of autophagy in skeleud muscle uncovers the accumulation of ubiquitinated proteins emd their potential role in muscle damage in Pompe disease. Hum Mol Genet 17(24) 3897-3908 Reuser AJ, Drost MR (2006) Lysosomal dysfunction, ceUular pathology and clinical symptoms basic principles. Acta Paediatr Suppl 95(451) 77-82 Sands MS, Haskins ME (2008) CNS-directed gene therapy for lysosomal storage diseases. Acta Paediatr Suppl 97(457) 22-27... 

Bahr BA, Bendiske, The neuropathogenic contributions of lysosomal dysfunction. J Neurochem 2002 83 481-489. 

Aldurazyme (tradename, also known as laronidase) is a recombinant version of one polymorphic variant of the human enzyme a-L-iduronidase. It was approved for general medical use in the USA in 2003 and is indicated for the treatment of patients with certain forms of the rare inherited disease MPS I. MPS I is caused by a deficiency of a lysosomal a-L-iduronidase, which normally catalyses the hydrolysis of terminal a-L-iduronic acid residues from the glycosaminoglycans dermatan sulfate and heparin sulfate. The deficiency results in accumulation of the glycosaminoglycans throughout the body, causing widespread cell and tissue dysfunction. 

Familial demyelinative/dysmyelinative and axonal neuropathies may also be caused by impaired lysosomal lipid metabolism. Metachromatic leukodystrophy (sulfatide lipidosis) results from mutations of the arylsulfatase A gene, which encodes a lysosomal enzyme required for sulfatide turnover. Myelin is affected in both CNS and PNS, though dysfunction is restricted to the PNS in some patients, and the onset of symptoms can occur at any time between infancy and adulthood. Bone marrow transplantation can slow disease progression and improve nerve conduction velocities [57]. (See in Ch. 41.)... 

Walkley, S. U. Pathogenic cascades in brain dysfunction. In F. M. Platt and S. U. Walkley (eds), Lysosomal Disorders of the Brain. New York Oxford University Press, 2004, pp. 290-324. 

Oxidized LDL alter cellular functions role in cell death Oxidized LDL seem to be poorly degraded by lysosomal enzymes and accumulate in lysosomes altering in turn their functionality (Dean et al., 1997). It has been proposed that inhibition of oxidized LDL degradation and subsequent lipid accumulation may induce a destabilization of the acidic compartment, and lysosomal rupture with a relocation of lysosomal enzymes in the cytosol (li W et al, 1998). This process, also called endopepsis , occurs early and could precede mitochondrial dysfunction and cell death (Lossel et al., 1994). Moreover, oxidized LDL trigger a dysfunction of the intracellular proteolytic ubiquitin/proteasome pathway (early activation followed by inhibition)... 

A detailed spectroscopic study has shown that swainsonine, from Swainsona canescens (Benth.) A. Lee, is 8a/3-indolizidine-la,2a,8 3-triol (1), and the structure and relative configuration have been confirmed by X-ray crystallography.1 Swainsonine is a potent inhibitor of a-mannosidase, and in animals it produces an accumulation of mannose-rich oligosaccharides in the lysosomal system of cells, leading to organ dysfunction and clinical disease.1... 

Fukuda T, Ewan L, Bauer M, Mattaliano RJ, Zaal K, Ralston E, Plotz PH, Raben N. Dysfunction of endocytic and autophagic pathways in a lysosomal storage disease. Ann Neurol 2006 59(4) 700-8. 

Walkley SU. Pathogenic cascades and brain dysfunction. In Lysosomal Storage Disorders of the Brain. Platt FM, Walkley SU, eds. 2004. Oxford University Press, New York. 

The acceptance by nephrologists of urinary enzyme activity as a measure of renal tubular dysfunction has been limited for several reasons. Paramount among these has been the difficulty to establish correlations between specific disease states and the presence or absence of enzymuria. In addition, a relationship between the severity of cellular injury and the magnitude or cellular source of the enzymuria has been difficult to establish. For example, enzymes that appear in the urine may originate from lysosomes, the brush-border membrane, and/or the cytoplasm of the cells. Moreover, various factors that alter urinary enzyme activity are independent of cellular integrity, i.e., urinary pH, osmolarity, and the presences of various enzyme inhibitors or activators [160]. 

After the initial binding to the anionic phospholipids of the PTC, the aminoglycoside molecule is quickly transferred to the transmembrane protein megalin and endocytosed [42, 43, 48-50, 52-59, 66-68, 72, 73]. Aminoglycosides enter the PTC on either the apical or basolateral plasma membrane via receptor-mediated endocytosis. and are ultimately sequestered in the same endosomal compartment [68]. In an experiment with LLC-PKl cells. Ford et al. demonstrated that aminoglycosides were internalized equally across the apical and basolateral membranes by receptor-mediated endocytosis. This was followed by colocalization within the lysosomal compartment and similar magnitudes of cellular dysfunction [68]. 

---