HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts.

Niemann-Pick type C1 (NPC1) disease is a lysosomal lipid storage disorder caused by mutations of the NPC1 gene. More than 300 disease-associated mutations are reported in patients, resulting in abnormal accumulation of unesterified cholesterol, glycosphingolipids, and other lipids in late endosomes and lysosomes (LE/Ly) of many cell types. Previously, we showed that treatment of many different NPC1 mutant fibroblasts with histone deacetylase inhibitors resulted in reduction of cholesterol storage, and we found that this was associated with enhanced exit of the NPC1 protein from the endoplasmic reticulum and delivery to LE/Ly. This suggested that histone deacetylase inhibitors may work through changes in protein chaperones to enhance the folding of NPC1 mutants, allowing them to be delivered to LE/Ly. In this study, we evaluated the effect of several HSP90 inhibitors on NPC1I1061T skin fibroblasts. We found that HSP90 inhibition resulted in clearance of cholesterol from LE/Ly, and this was associated with enhanced delivery of the mutant NPC1I1061T protein to LE/Ly. We also observed that inhibition of HSP90 increased the expression of HSP70, and overexpression of HSP70 also reduced cholesterol storage in NPC1I1061T fibroblasts. However, we did not see correction of cholesterol storage by arimoclomol, a drug that is reported to increase HSP70 expression, at doses up to 0.5 mM. The increase in other chaperones as a consequence of HSP90 improves folding of NPC1 protein and relieves cholesterol accumulation in NPC1 mutant fibroblasts.

Nrf2 deletion results in impaired performance in memory tasks and hyperactivity in mature and aged mice.

Oxidative stress has been implicated in both the functional and cognitive decline associated with neuropsychiatric diseases and aging. A master regulator of the body's defense mechanism against oxidative stress is nuclear factor erythroid 2-related factor (NRF2). Here we investigated the effects of NRF2 deletion on motor and cognitive performance in "Aged" mice (17-25 months old) as compared to "Mature" mice (3-15 months old). We observed that the Aged Nrf2-/- mice were hyperactive and exhibited impaired acquisition of an active avoidance response. Furthermore, the Mature mice also displayed a hyperactive phenotype and had impaired working memory in the probe trial of the water radial arm maze. Overall, it appears that NRF2 may be implicated in memory and activity functions and its deletion exacerbates deficits associated with aging. These observations provide a model for assessing the role of oxidative stress in age-related disorders.