Progressive Volume Loss and White Matter Degeneration in Cstb-Deficient Mice: A Diffusion Tensor and Longitudinal Volumetry MRI Study

Peer reviewe

Genome-wide association study of white-coat effect in hypertensive patients

Background: White-coat effect (WCE) confounds diagnosis and treatment of hypertension. The prevalence of white-coat hypertension is higher in Europe and Asia compared to other continents suggesting that genetic factors could play a role. Methods: To study genetic variation affecting WCE, we conducted a two-stage genome-wide association study involving 1343 Finnish subjects. For the discovery stage, we used Genetics of Drug Responsiveness in Essential Hypertension (GENRES) cohort (n = 206), providing the mean WCE values from up to four separate office/ambulatory recordings conducted on placebo. Associations with p values <1 × 10−5 were included in the replication step in three independent cohorts: Haemodynamics in Primary and Secondary Hypertension (DYNAMIC) (n = 182), Finn-Home study (n = 773) and Dietary, Lifestyle and Genetic Determinants of Obesity and Metabolic Syndrome (DILGOM) (n = 182). Results: No single nucleotide polymorphisms reached genome-wide significance for association with either systolic or diastolic WCE. However, two loci provided suggestive evidence for association. A known coronary artery disease risk locus rs2292954 in SPG7 associated with systolic WCE (discovery p value = 2.2 × 10−6, replication p value = 0.03 in Finn-Home, meta-analysis p value 2.6 × 10−4), and rs10033652 in RASGEF1B with diastolic WCE (discovery p value = 4.9 × 10−6, replication p value = 0.04 in DILGOM, meta-analysis p value = 5.0 × 10−3). Conclusion: This study provides evidence for two novel candidate genes, SPG7 and RASGEF1B, associating with WCE. Our results need to be validated in even larger studies carried out in other populations

The PDE1/5 Inhibitor SCH-51866 Does Not Modify Disease Progression in the R6/2 Mouse Model of Huntington's Disease

Huntington’s disease is a neurodegenerative disorder caused by mutations in the CAG tract of huntingtin. Several studies in HD cellular and rodent systems have identified disturbances in cyclic nucleotide signaling, which might be relevant to pathogenesis and therapeutic intervention. To investigate whether selective phosphodiesterase (PDE) inhibitors can improve some aspects of disease pathogenesis in HD models, we have systematically evaluated the effects of a variety of cAMP and cGMP selective PDE inhibitors in various HD models. Here we present the lack of effect in a variety of endpoints of the PDE subtype selective inhibitor SCH-51866, a PDE1/5 inhibitor, in the R6/2 mouse model of HD, after chronic oral dosing

Genetic Deletion of Transglutaminase 2 Does Not Rescue the Phenotypic Deficits Observed in R6/2 and zQ175 Mouse Models of Huntington's Disease

<div><p>Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disorder caused by expansion of CAG repeats in the huntingtin gene. Tissue transglutaminase 2 (TG2), a multi-functional enzyme, was found to be increased both in HD patients and in mouse models of the disease. Furthermore, beneficial effects have been reported from the genetic ablation of TG2 in R6/2 and R6/1 mouse lines. To further evaluate the validity of this target for the treatment of HD, we examined the effects of TG2 deletion in two genetic mouse models of HD: R6/2 CAG 240 and zQ175 knock in (KI). Contrary to previous reports, under rigorous experimental conditions we found that TG2 ablation had no effect on either motor or cognitive deficits, or on the weight loss. In addition, under optimal husbandry conditions, TG2 ablation did not extend R6/2 lifespan. Moreover, TG2 deletion did not change the huntingtin aggregate load in cortex or striatum and did not decrease the brain atrophy observed in either mouse line. Finally, no amelioration of the dysregulation of striatal and cortical gene markers was detected. We conclude that TG2 is not a valid therapeutic target for the treatment of HD.</p></div

Mean number of days required to obtain 40 reinforcers across two consecutive sessions during the training phase (n = 6–12 per genotype).

<p>*Significant HD genotype effect. WT: wild-type, TG2−/−: homozygous TG2 knockout, HET: zQ175 HET.</p

Overall visit frequency detected in the PhenoCube system as a function of genotype, age and light cycle phase in animals from the zQ175×TG2 KO line.

<p>*Significant HD genotype differences regardless of the light phase (in the mean path length the differences were detected between HET and WT animals); ##significant differences due to light phase in the cycle independently of genotype; ∧significant TG2 genotype differences (see results method for details). WT: wild-type, TG2−/−: homozygous TG2 knockout, HET: zQ175 HET, HOM: zQ175 HOM.</p

The relative striatal (left panels) and cortical (right panels) mRNA expression level of mice examined from the R6/2×TG2 KO line at 12 weeks of age (n = 12 per genotype).

<p>Relative mRNA levels are normalized to WT controls. For normalization, the geometric means of <i>Ubc</i>, <i>Eif4a2</i> an <i>Atp5b</i> were used. *Significant HD Genotype effect; #significant TG2 Genotype effect. WT: wild-type, TG2+/−: heterozygous TG2 knockout, TG2−/−: homozygous TG2 knockout.</p

Behavioral data captured in the PhenoCube system as a function of genotype, age and light cycle phase in animals from the R6/2×TG2 KO line.

<p>A. Overall visit frequency. B. Mean path length. C. Percent alternations (Data for this measure were not collected at 16 weeks of age since R6/2 mice were not tested in this protocol due to reduced licking). *Significant HD genotype differences within each light phase, at each age; #: significant differences due to light phase in the diurnal cycle in the WT mice; ##significant differences due to light phase in the cycle for each age independently of genotype; ###significant differences due to light phase in the diurnal cycle in the R6/2 mice; ∧significant TG2 genotype differences. WT: wild-type, TG2+/−: heterozygous TG2 knockout, TG2−/−: homozygous TG2 knockout.</p