Lessons learnt from animal models: pathophysiology of neuropathic lysosomal storage disorders

Abstract

Approximately 50 inborn errors of metabolism known as lysosomal storage disorders have been discovered to date, most of which are due to a single mutation in a gene encoding a soluble lysosomal enzyme. Consequently, inadequate enzyme activity results in the accumulation of substrates for that enzyme, invariably accompanied by a wide variety of secondary pathological changes. Many of these conditions remain untreatable, and therefore, research into pathogenic processes and potential treatment strategies is intense. A key tool for researchers in this area is the availability of clinically relevant animal models in which to study disease manifestation and evaluate therapeutic outcomes. Large numbers of both naturally occurring and genetically modified animal models of neurodegenerative lysosomal storage disorders are in existence, with spontaneous models occurring in both large domestic (e.g., cat, dog, sheep) and small (e.g., mouse) animal species. Many have undergone rigorous phenotypic characterization and are now providing us with insights into neurological disease processes. The purpose of this review is to highlight some of the major lessons learnt from these studies.

Gemfibrozil and Fenofibrate, Food and Drug Administration-approved Lipid-lowering Drugs, Up-regulate Tripeptidyl-peptidase 1 in Brain Cells via Peroxisome Proliferator-activated Receptor α

“…The NCL family of disease can be considered to be one of the most important hereditary neurodegenerative lysosomal storage diseases in children (34). Mutations in the Cln2 gene result in deficiency or loss of function of the TPP1 enzyme (9,30,35).…”

Selective Yolk Deposition and Mannose Phosphorylation of Lysosomal Glycosidases in Zebrafish

“…The anti-human acid ␣-glucosidase monoclonal antibody was used at a 1:2500 dilution and the anti-HPC4 antibody at a 1:500 dilution. The blocking process was performed in the presence of 1 mM CaCl 2 .…”

“…Lysosomal catabolism and the subsequent recycling and utilization of metabolites are critical for many biological processes, as highlighted by the serious consequences to human and animal health when these functions are disrupted (1,2). Degradation of macromolecules by lysosomal hydrolases is also essential for the utilization of the yolk during embryogenesis in fish, insects, and amphibians.…”

“…The cytoplasm of this yolk cell contains glycogen and protein granules, the latter of which is composed mainly of the yolk glycophosphoprotein, vitellogenin (Vtg). 2 This large multidomain protein is synthesized by the maternal liver, secreted into the bloodstream, internalized by the growing oocyte via receptor-mediated endocytosis, and then stored in specialized organelles, the yolk granules (yolk platelets) (3)(4)(5). In addition to vitellogenin, several other complex sialoglycoproteins and glycolipids have been characterized in the eggs of aquatic species, although their biological roles are not yet fully understood (6,7).…”

21. Glycan-based biomarkers for the mucopolysaccharidoses

“…We refer the reader to other recent reviews that cover other types of biomarkers based on enzyme mass, enzyme activity and pathological consequences of disease [19][20][21][22]. Unique glycan structures have long been associated with initiation and progression of diverse diseases, including cancer and inflammation [23].…”