Therapeutic strategies to ameliorate lysosomal storage disorders--a focus on Gaucher disease.

The lysosomal storage disorders encompass more than 40 distinct diseases, most of which are caused by the deficient activity of a lysosomal hydrolase leading to the progressive, intralysosomal accumulation of substrates such as sphingolipids, mucopolysaccharides, and oligosaccharides. Here, we primarily focus on Gaucher disease, one of the most prevalent lysosomal storage disorders, which is caused by an impaired activity of glucocerebrosidase, resulting in the accumulation of the glycosphingolipid glucosylceramide in the lysosomes. Enzyme replacement and substrate reduction therapies have proven effective for Gaucher disease cases without central nervous system involvement. We discuss the promise of chemical chaperone therapy to complement established therapeutic strategies for Gaucher disease. Chemical chaperones are small molecules that bind to the active site of glucocerebrosidase variants stabilizing their three-dimensional structure in the endoplasmic reticulum, likely preventing their endoplasmic reticulum-associated degradation and allowing their proper trafficking to the lysosome where they can degrade accumulated substrate to effectively ameliorate Gaucher disease.

Similar activation of glial cultures from different rat brain regions by neuroinflammatory stimuli and downregulation of the activation by a new class of small molecule ligands.

Activated glia (astrocytes and microglia) surrounding neuritic plaques in Alzheimer's disease (AD) overexpress an array of detrimental inflammatory molecules. Chronically activated glia and numerous inflammatory mediators in AD suggest that neuroinflammation is an integral component of the pathogenic process. However, the potential for glia from different brain regions to respond differentially to activating stimuli and inhibitors of glial activation is not well understood. As part of our goal to elucidate molecular mechanisms of glial activation, we examined the activation responses of primary cultures of glia derived from different brain regions. Neonatal rat glia from cortex, hippocampus, midbrain, brainstem, striatum, and cerebellum can be activated by a variety of stimuli (including beta-amyloid, S100B, and lipopolysaccharide), and the activation can be downregulated by a new class of small molecule, cell permeable ligands. The end points assayed included IL-1beta, iNOS, apoE and the astrocyte marker protein GFAP. The activating stimuli were able to increase the production of iNOS and IL1beta, and the ligand was able to inhibit this increase in cultures derived from the diverse brain regions. The activation and downregulation were selective, as demonstrated by lack of effect on GFAP levels and no downregulation of apoE. These results are consistent with the working hypothesis that regional differences in glial activation seen in disease and injury are reflective of the intensity, duration and repertoire of activating stimuli rather than an innate property of the glia.