Adipose storage deficiency in lysosomal storage disease

Cellular material, and the energy it contains, flows into lysosomes within cells to be broken down into raw materials. The bulle of those raw materials are exported into the cytosol for reuse. In lysosomal storage disease this process is blocked entirely for some material and likely reduced for others. As a result, the lysosome fills with partially degraded material that remains undegraded. More proteins and membranes are produced to store this material and to provide more lysosomes. In addition, the material that normally would be recycled and reused now has to be synthesized de novo probably contributing to the adipose deficient phenotype observed in MPSI, MPSIIIB, MPSVII, NPAB, and INCL mice. In MPSI mice, this results in an apparent depletion of cellular energy stores and redistribution of that energy in the form of glycosaminoglycans in lysosomes as well as increased lysosomal membranes and proteins. Short-term enzyme replacement therapy (48hrs) restores normal energy flow and recycling allowing for the reestablishment of normal cellular stores of energy. Lysosomal flux may play an important yet unheralded role in the spectrum between leanness and obesity. More importantly, in the case of lysosomal storage diseases, the amount of energy devoted to storing the undegraded lysosomal material in membranous structures will increase over time. Providing a higher caloric density diet may help cellular energy stores to return to more normal levels and forestall death due to possible cellular energy depletion.