Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress

The occurrence of repeat-associated non-ATG (RAN) translation, an atypical form of translation of expanded repeats that results in the synthesis of homopolymeric expansion proteins, is becoming more widely appreciated among microsatellite expansion disorders. Such disorders include amyotrophic lateral sclerosis and frontotemporal dementia caused by a hexanucleotide repeat expansion in the C9ORF72 gene (c9FTD/ALS). We and others have recently shown that this bidirectionally transcribed repeat is RAN translated, and the “c9RAN proteins” thusly produced form neuronal inclusions throughout the central nervous system of c9FTD/ALS patients. Nonetheless, the potential contribution of c9RAN proteins to disease pathogenesis remains poorly understood. In the present study, we demonstrate that poly(GA) c9RAN proteins are neurotoxic and may be implicated in the neurodegenerative processes of c9FTD/ALS. Specifically, we show that expression of poly(GA) proteins in cultured cells and primary neurons leads to the formation of soluble and insoluble high molecular weight species, as well as inclusions composed of filaments similar to those observed in c9FTD/ALS brain tissues. The expression of poly(GA) proteins is accompanied by caspase-3 activation, impaired neurite outgrowth, inhibition of proteasome activity, and evidence of endoplasmic reticulum (ER) stress. Of importance, ER stress inhibitors, salubrinal and TUDCA, provide protection against poly(GA)-induced toxicity. Taken together, our data provide compelling evidence towards establishing RAN translation as a pathogenic mechanism of c9FTD/ALS, and suggest that targeting the ER using small molecules may be a promising therapeutic approach for these devastating diseases.     

Diurnal salivary cortisol and urinary catecholamines are associated with diabetes mellitus: the Multi-Ethnic Study of Atherosclerosis

The objective was to examine the cross-sectional association of diurnal salivary cortisol curve components and urinary catecholamines with diabetes status. Up to 18 salivary cortisol samples over 3 days and overnight urinary catecholamines were collected from 1002 participants in the Multi-Ethnic Study of Atherosclerosis. Diabetes was defined as a fasting blood glucose of at least 126 mg/dL or medication use. Cortisol curve measures included awakening cortisol, cortisol awakening response, early decline, late decline, and cortisol area under the curve (AUC). Urinary catecholamines included epinephrine, norepinephrine, and dopamine. Participants with diabetes had significantly lower cortisol awakening response (β = -0.19; 95% confidence interval [CI], -0.34 to -0.04) than those without diabetes in multivariable models. Whereas men with diabetes had a nonsignificant trend toward lower total AUC (β = -1.56; 95% CI, -3.93 to 0.80), women with diabetes had significantly higher total AUC (β = 2.62; 95% CI, 0.72 to 4.51) (P = .02 for interaction) compared with those without diabetes. Men but not women with diabetes had significantly lower urinary catecholamines compared with those without diabetes (P < .05). Diabetes is associated with neuroendocrine dysregulation, which may differ by sex. Further studies are needed to determine the role of the neuroendocrine system in the pathophysiology of diabetes.     

Suggestive evidence for association between L‐type voltage‐gated calcium channel (CACNA1C) gene haplotypes and bipolar disorder in Latinos: a family‐based association study

Objectives: Through recent genome‐wide association studies (GWASs), several groups have reported significant association between variants in the calcium channel, voltage‐dependent, L‐type, alpha 1C subunit (CACNA1C) and bipolar disorder (BP) in European and European‐American cohorts. We performed a family‐based association study to determine whether CACNA1C is associated with BP in the Latino population. Methods: This study included 913 individuals from 215 Latino pedigrees recruited from the USA, Mexico, Guatemala, and Costa Rica. The Illumina GoldenGate Genotyping Assay was used to genotype 58 single‐nucleotide polymorphisms (SNPs) that spanned a 602.9‐kb region encompassing the CACNA1C gene including two SNPs (rs7297582 and rs1006737) previously shown to associate with BP. Individual SNP and haplotype association analyses were performed using Family‐Based Association Test (version 2.0.3) and Haploview (version 4.2) software. Results: An eight‐locus haplotype block that included these two markers showed significant association with BP (global marker permuted p = 0.0018) in the Latino population. For individual SNPs, this sample had insufficient power (10%) to detect associations with SNPs with minor effect (odds ratio = 1.15). Conclusions: Although we were not able to replicate findings of association between individual CACNA1C SNPs rs7297582 and rs1006737 and BP, we were able to replicate the GWAS signal reported for CACNA1C through a haplotype analysis that encompassed these previously reported significant SNPs. These results provide additional evidence that CACNA1C is associated with BP and provides the first evidence that variations in this gene might play a role in the pathogenesis of this disorder in the Latino population.     

PP2A Ligand ITH12246 Protects against Memory Impairment and Focal Cerebral Ischemia in Mice

相似文献