Finding pathogenic commonalities between Niemann-Pick type C and other lysosomal storage disorders: Opportunities for shared therapeutic interventions.

Lysosomal storage disorders (LSDs) are diseases characterized by the accumulation of macromolecules in the late endocytic system and are caused by inherited defects in genes that encode mainly lysosomal enzymes or transmembrane lysosomal proteins. Niemann-Pick type C disease (NPCD), a LSD characterized by liver damage and progressive neurodegeneration that leads to early death, is caused by mutations in the genes encoding the NPC1 or NPC2 proteins. Both proteins are involved in the transport of cholesterol from the late endosomal compartment to the rest of the cell. Loss of function of these proteins causes primary cholesterol accumulation, and secondary accumulation of other lipids, such as sphingolipids, in lysosomes. Despite years of studying the genetic and molecular bases of NPCD and related-lysosomal disorders, the pathogenic mechanisms involved in these diseases are not fully understood. In this review we will summarize the pathogenic mechanisms described for NPCD and we will discuss their relevance for other LSDs with neurological components such as Niemann- Pick type A and Gaucher diseases. We will particularly focus on the activation of signaling pathways that may be common to these three pathologies with emphasis on how the intra-lysosomal accumulation of lipids leads to pathology, specifically to neurological impairments. We will show that although the primary lipid storage defect is different in these three LSDs, there is a similar secondary accumulation of metabolites and activation of signaling pathways that can lead to common pathogenic mechanisms. This analysis might help to delineate common pathological mechanisms and therapeutic targets for lysosomal storage diseases.

Photodamage attenuation effect by a tetraprenyltoluquinol chromane meroterpenoid isolated from Sargassum muticum.

A tetraprenyltoluquinol meroterpenoid with a chromane moiety, obtained as an epimeric mixture at C3, was isolated for the first time from the dichloromethane fraction of a methanolic extract from the brown alga Sargassum muticum. The structure has been established by means of spectral methods including NMR spectroscopy and MS and comparison with reported data. The compound showed photodamage attenuation on irradiated cells with UVA light, presented protection against intracellular ROS generation in a degree comparable to retinoic acid (9.1-20.6%) and did not display toxicity against human dermal fibroblast cells.

The value of genetic polymorphisms to predict toxicity in metastatic colorectal patients with irinotecan-based regimens.

PURPOSE: We are trying to identify predictive factors of high risk of toxicity by analyzing candidate genes in the irinotecan pathways in order to identify useful tools to improve mCRC patient management under real practice conditions. METHODS: Genomic DNA was genotyped for UGT1A1 (*28, *60 and *93) from all 101 patients, and irinotecan dose was 180 mg/m(2) every second week. Clinical data were obtained by retrospective chart review. The primary endpoint is to find out whether the pharmacogenetic test in the clinical practice may predict toxicity. RESULTS: Grade 3/4 diarrhea occurred in twelve patients and required dose reduction in six patients, and neutropenia reached grade 3/4 in 19 patients (only one patient with *28/*28 genotype). The UGT1A1*93 seemed to relate with grade 3/4 neutropenia but only in the heterozygote state (G/A), p = 0.071, and UGT1A*60 showed no association with neutropenia. Twenty-eight percentage of patients required the use of G-CSF; 64.3% of them harbored *1/*28 or *28/*28 genotypes, p = 0.003. Thirty-seven (36.6%) patients required dose reduction of irinotecan and/or 5-FU owing to toxicity, mainly neutropenia and diarrhea. No significant association was detected between *28, *60 and *93 UGT1A variants and severe irinotecan-associated hematologic or GI toxicity. CONCLUSION: The impact of increased risk of toxicity attributed to the UGT1A variants may be offset by irinotecan in clinical practice by dose reduction or the use of colony-stimulating factor.

Female infertility due to anovulation and defective steroidogenesis in NPC2 deficient mice.

Niemann Pick C2 (NPC2) and NPC1 proteins function cooperatively to catalyze cholesterol efflux from lysosomes. NPC1 is expressed in ovarian cells and female NPC1 mice are infertile. This work addressed for the first time the localization and function of murine NPC2 protein in the ovary. Ovarian NPC2 was localized to theca and luteal cells, which use cholesterol as a substrate to produce estradiol and progesterone, respectively. NPC2 deficient (NPC2-/-) females had abnormal estrous cycles and were infertile, with normal folliculogenesis until the antral stage, but a complete absence of corpora lutea and many zonae pellucidae remnants, indicative of anovulation. Serum estradiol was reduced and ovarian cholesterol was accumulated in NPC2-/- mice, suggesting a defect in cholesterol export from intracellular stores. After superovulation, NPC2-/- mice ovulated less eggs than their wild type littermates, showed ovaries with less corpora lutea and numerous unruptured follicles, and lower serum progesterone concentration. Together, these results suggest that NPC2 participates in the traffic of ovarian cholesterol required to provide the substrate for steroid synthesis and support follicle maturation, ovulation and luteinization.