THE CELL BIOLOGY OF LYSOSOMAL STORAGE DISORDERS Nature Reviews Molecular Cell Biology 5, 554 -565 (2004); doi:10.1038/nrm1423 | |
 Рис.1. | Fig. 1. An overview of epidermal development. In mice, the development of the epidermis and hair happens simultaneously just before and just after birth. Around E9, the first signals to make a placode are transduced to the epidermis. Placodes form around E15 and the formation of a hair follicle, morphogenesis continues until day 9 post partum, at which point the hair cycle starts with the the catagen-telogen transition around 16 days post partum. During the same time, the epidermis forms into an impermeable barrier from a single layer of cells around E9. An intact epidermis is formed, complete with cornified layer just prior to birth. The diseases which show their first effects at particular time points are shown in blue. DC, dermal condensate; DP, dermal papilla.  Рис.2. | The biochemical and cellular basis of lysosomal storage disorders. Most mutations in 'classic' lysosomal storage disorders (LSDs) result in the delivery of a defective enzyme that has a reduced catalytic activity to lysosomes (label 1). In some cases, another protein that is required for optimal hydrolase activity is defective or absent (label 2). An LSD can be caused by the defective transport of a lysosomal hydrolase out of the endoplasmic reticulum (ER) due to a mutation that causes misfolding (label 3). Alternatively, an LSD can be caused by the defective transport of a lysosomal hydrolase out of the ER because a multi-enzyme complex that is required for transport cannot form (label 4). In the Golgi, defective glycosylation could result in an enzyme with reduced catalytic activity (label 5). Alternatively, defective glycosylation in the Golgi could produce an enzyme that cannot reach lysosomes because it cannot bind to mannose-6-phosphate receptors (due to defective glycosylation with mannose-6-phosphate; label 6). Defects in other transport steps from the Golgi could also lead to an LSD (label 7). Several LSDs are caused by defects in integral lysosomal membrane proteins. These include defects in transporters (label 8), or in proteins that are involved in other vital regulatory events of lysosomal function (label 9). In this figure lysosomal hydrolases are shown in various shades of blue, and a relevant LSD example is shown for each defect when one is known. For further details, please refer to the main text.  Рис.3. | A possible roadmap of the pathology of lysosomal storage disorders. Lysosomal storage disorders (LSDs) are all characterized by the intra-lysosomal accumulation of unmetabolized substrates, which is the primary cause of the disease. However, the extensive range of disease symptoms indicates that many secondary biochemical and cellular pathways must also be activated. So, the primary accumulating metabolite affects a secondary biochemical or cellular pathway, which then subsequently causes tissue pathology, altered gene expression and the activation of tertiary biochemical pathways. Please refer to the main text for further details  Рис.4. | Therapies for lysosomal storage disorders. Lysosomal storage disorder (LSD) treatments can be divided into those that directly modify the defective enzyme (red), those that reduce the levels of biosynthesis of the accumulating substrate (yellow), general treatments that deal mainly with the symptoms (green) and potential new therapies that will be based on intervening in downstream cellular pathways that are modified in LSDs (blue). Treatments that are framed in purple are in clinical use at present. With respect to treatments that directly modify the defective lysosomal hydrolase, recent studies have focused on the design of small molecules that are able to reactivate defective enzymes90, 91. The study of these so-called 'chemical chaperones' has received impetus from work showing that defective -glucosidase could be reactivated in a Gaucher-disease model107. However, a significant amount of work is still required before this approach can become a real therapeutic option for LSDs.  Box 1. |  Box 3. | Lysosomes and lysosomal storage disorders Табл.1 Lysosomal storage disorders LinksDATABASES| | | | | | | | | | | | | | | | | | Supplementary information | Нарушения, которых известно более 40, обусловлены неправильной активностью лизосомных белков, в результате чего внутри лизосом происходит накопление нераспавшихся до конца метаболитов. Генетические и молекулярные основы lysosomal storage disorders известны плохо, неясны события, которые ведут от накопления внутри лизосом метаболитов к патологии. Обсуждаются нижестоящие клеточные пути, которые потенциально затронуты в этих нарушениях это м. помочь выявить их патологические механизмы. |