Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

To date, a mutation of the glucocerebrosidase gene (GBA) is the strongest genetic risk factor associated to Parkinson’s disease (PD). This leads to my prospective cohort study of a GBA mutation positive cohort for early features of PD. This study indicates that as a group, GBA mutation positive individuals show deterioration in clinical markers consistent with the prodrome of PD. I have generated cell culture models from individuals within the clinical cohort studied, in order to delineate the molecular mechanism of mutant GBA to the pathogenesis of PD. My results on skin fibroblast cultures reproduce the glucocerebrosidase enzyme (GCase) enhancement seen from previous studies following treatment with pharmacological chaperone (PC) molecules. These data further provide support for a link between GBA mutations and changes in the autophagic/lysosomal system, which could predispose to neurodegeneration. Due to the limitation of fibroblasts as a model for interrogating the complete pathway in PD, I studied human adipose neural crest stem cell (NCSC) derived dopaminergic (DA) neurons. This model recapitulated the defects identified in the fibroblast model including: reductions in GCase activity and protein level, and lysosomal abnormalities including impairments of autophagy. In addition, reduced GCase was associated with increased α-synuclein (SNCA). PC treatment restored GCase function, upregulated macroautophagy and lead to a reduction in SNCA levels. PC therapy could represent a novel therapeutic approach for PD

Single nucleotide polymorphisms in bone turnover-related genes in Koreans: ethnic differences in linkage disequilibrium and haplotype

<p>Abstract</p> <p>Background</p> <p>Osteoporosis is defined as the loss of bone mineral density that leads to bone fragility with aging. Population-based case-control studies have identified polymorphisms in many candidate genes that have been associated with bone mass maintenance or osteoporotic fracture. To investigate single nucleotide polymorphisms (SNPs) that are associated with osteoporosis, we examined the genetic variation among Koreans by analyzing 81 genes according to their function in bone formation and resorption during bone remodeling.</p> <p>Methods</p> <p>We resequenced all the exons, splice junctions and promoter regions of candidate osteoporosis genes using 24 unrelated Korean individuals. Using the common SNPs from our study and the HapMap database, a statistical analysis of deviation in heterozygosity depicted.</p> <p>Results</p> <p>We identified 942 variants, including 888 SNPs, 43 insertion/deletion polymorphisms, and 11 microsatellite markers. Of the SNPs, 557 (63%) had been previously identified and 331 (37%) were newly discovered in the Korean population. When compared SNPs in the Korean population with those in HapMap database, 1% (or less) of SNPs in the Japanese and Chinese subpopulations and 20% of those in Caucasian and African subpopulations were significantly differentiated from the Hardy-Weinberg expectations. In addition, an analysis of the genetic diversity showed that there were no significant differences among Korean, Han Chinese and Japanese populations, but African and Caucasian populations were significantly differentiated in selected genes. Nevertheless, in the detailed analysis of genetic properties, the LD and Haplotype block patterns among the five sub-populations were substantially different from one another.</p> <p>Conclusion</p> <p>Through the resequencing of 81 osteoporosis candidate genes, 118 unknown SNPs with a minor allele frequency (MAF) > 0.05 were discovered in the Korean population. In addition, using the common SNPs between our study and HapMap, an analysis of genetic diversity and deviation in heterozygosity was performed and the polymorphisms of the above genes among the five populations were substantially differentiated from one another. Further studies of osteoporosis could utilize the polymorphisms identified in our data since they may have important implications for the selection of highly informative SNPs for future association studies.</p

Using radiocarbon to determine the mycorrhizal status of fungi

Measurements of C-13 in fungal sporocarps are useful in assessing mycorrhizal or saprotrophic status. Because C-14 measurements can indicate the age of fungal carbon (C) and mycorrhizal fungi depend closely on recent photosynthate, C-14 may provide additional insight into possible mycorrhizal status. Sporocarps, needles, and litter from Woods Creek, OR, USA together with archived sporocarps were measured for C-14 content by accelerator mass spectrometry. Known mycorrhizal fungi resembled current-year needles (Amanita, Cantharellus and Gomphidius) or atmospheric CO₂ (Tuber) in C-14 and indicated an average age of 0-2 yr for incorporated C, whereas saprotrophic genera (Pleurocybella , Lepiota and Hypholoma) were composed of C at least 10 yr old. Of genera tentatively considered mycorrhizal from previous work with C-13, only Otidia and Sowerbyella appeared mycorrhizal from C-14 measurements, whereas Aleuria, Clavulina, Paurocotylis and Ramaria (sensu lato) consisted of older carbon and were presumably saprotrophic. C-14 clearly separated known mycorrhizal or saprotrophic fungi and indicated C-13 measurements should be interpreted cautiously on species of unknown status. C-14 results for needles and mycorrhizal fungi suggested that C sources other than atmospheric CO₂ may contribute small amounts of C. Possible sources include storage of carbohydrates and amino acids, organic nitrogen uptake, and incorporation of soil-respired CO₂ by anaplerotic or photosynthetic pathways