Neuronopathic GBA1L444P Mutation Accelerates Glucosylsphingosine Levels and Formation of Hippocampal Alpha-Synuclein Inclusions.

The most common genetic risk factor for Parkinson's disease (PD) is heterozygous mutations GBA1, which encodes for the lysosomal enzyme, glucocerebrosidase. Reduced glucocerebrosidase activity associates with an accumulation of abnormal α-synuclein (α-syn) called Lewy pathology, which characterizes PD. PD patients heterozygous for the neuronotypic GBA1L444P mutation (GBA1+/L444P) have a 5.6-fold increased risk of cognitive impairments. In this study, we used GBA1+/L444P mice of either sex to determine its effects on lipid metabolism, expression of synaptic proteins, behavior, and α-syn inclusion formation. At 3 months of age, GBA1+/L444P mice demonstrated impaired contextual fear conditioning, and increased motor activity. Hippocampal levels of vGLUT1 were selectively reduced in GBA1+/L444P mice. We show, using mass spectrometry, that GBA1L444P expression increased levels of glucosylsphingosine, but not glucosylceramide, in the brains and serum of GBA1+/L444P mice. Templated induction of α-syn pathology in mice showed an increase in α-syn inclusion formation in the hippocampus of GBA1+/L444P mice compared with GBA1+/+ mice, but not in the cortex, or substantia nigra pars compacta. Pathologic α-syn reduced SNc dopamine neurons by 50% in both GBA1+/+ and GBA1+/L444P mice. Treatment with a GlcCer synthase inhibitor did not affect abundance of α-syn inclusions in the hippocampus or rescue dopamine neuron loss. Overall, these data suggest the importance of evaluating the contribution of elevated glucosylsphingosine to PD phenotypes. Further, our data suggest that expression of neuronotypic GBA1L444P may cause defects in the hippocampus, which may be a mechanism by which cognitive decline is more prevalent in individuals with GBA1-PD.SIGNIFICANCE STATEMENT Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are both pathologically characterized by abnormal α-synuclein (α-syn). Mutant GBA1 is a risk factor for both PD and DLB. Our data show the expression of neuronotypic GBA1L444P impairs behaviors related to hippocampal function, reduces expression of a hippocampal excitatory synaptic protein, and that the hippocampus is more susceptible to α-syn inclusion formation. Further, our data strengthen support for the importance of evaluating the contribution of glucosylsphingosine to PD phenotypes. These outcomes suggest potential mechanisms by which GBA1L444P contributes to the cognitive symptoms clinically observed in PD and DLB. Our findings also highlight the importance of glucosylsphingosine as a relevant biomarker for future therapeutics.

The effect of breed and diet type on the global transcriptome of hepatic tissue in beef cattle divergent for feed efficiency.

BACKGROUND: Feed efficiency is an important economic and environmental trait in beef production, which can be measured in terms of residual feed intake (RFI). Cattle selected for low-RFI (feed efficient) have similar production levels but decreased feed intake, while also emitting less methane. RFI is difficult and expensive to measure and is not widely adopted in beef production systems. However, development of DNA-based biomarkers for RFI may facilitate its adoption in genomic-assisted breeding programmes. Cattle have been shown to re-rank in terms of RFI across diets and age, while also RFI varies by breed. Therefore, we used RNA-Seq technology to investigate the hepatic transcriptome of RFI-divergent Charolais (CH) and Holstein-Friesian (HF) steers across three dietary phases to identify genes and biological pathways associated with RFI regardless of diet or breed. RESULTS: Residual feed intake was measured during a high-concentrate phase, a zero-grazed grass phase and a final high-concentrate phase. In total, 322 and 33 differentially expressed genes (DEGs) were identified across all diets for CH and HF steers, respectively. Three genes, GADD45G, HP and MID1IP1, were differentially expressed in CH when both the high-concentrate zero-grazed grass diet were offered. Two canonical pathways were enriched across all diets for CH steers. These canonical pathways were related to immune function. CONCLUSIONS: The absence of common differentially expressed genes across all dietary phases and breeds in this study supports previous reports of the re-ranking of animals in terms of RFI when offered differing diets over their lifetime. However, we have identified biological processes such as the immune response and lipid metabolism as potentially associated with RFI divergence emphasising the previously reported roles of these biological processes with respect to RFI.

Sex differences in incidence and mortality of bladder and kidney cancers: national estimates from 49 countries.

OBJECTIVES: In the United States, among patients diagnosed with bladder cancer (BC), women have increased disease-specific mortality compared with men. The main objective of this study was to determine whether this pattern is also present in other countries. For comparison, similar analyses were performed for kidney cancer (KC). METHODS AND MATERIALS: Data for this study were obtained from the GLOBOCAN 2008 database. A total of 49 countries with available information on BC and KC incidence and mortality were included in the analysis, representing all major geographic regions except Africa. For each country, we computed the sex-specific ratio of the total number of deaths from a given cancer to the total number of diagnoses in the year 2008 (the mortality-to-incidence ratio [MIR]). The relative MIR was computed for each country as a ratio of MIR in women to MIR in men. A relative MIR of more than 1 would indicate that the number of cancer-specific deaths relative to the number of cancer-specific diagnoses is greater in women than in men. RESULTS: For BC, the relative MIRs were significantly more than 1 in 26 countries (53%), significantly less than 1 in 2 countries (4%), and not significantly different from 1 in 21 countries (43%). The median relative MIR was 1.21 (interquartile range: 1.04-1.41). For KC, the relative MIRs were significantly more than 1 in 4 countries (8%), significantly less than 1 in 3 countries (6%), and not significantly different from 1 in 42 countries (86%). The median relative MIR was 1.00 (interquartile range: 0.94-1.06). CONCLUSION: Among BC patients, increased disease-specific mortality in women compared with men appears to be a common (although not a universal) phenomenon. This pattern may potentially be explained by differences between the sexes in the biology of disease, time to diagnosis, treatment decisions, and other factors. In contrast, among KC patients, no significant differences in disease-specific mortality were seen between the 2 sexes in the overwhelming majority of the countries.