Differential expression of alpha-synuclein in the hippocampus of SHR and SLA16 isogenic rat strains.

Two inbred strains, Lewis (LEW) and Spontaneously Hypertensive Rats (SHR), are well-known for their contrasting behavior related to anxiety/emotionality. Studies with these two strains led to the discovery of the Quantitative Trait Loci (QTL) on chromosome 4 (Anxrr16). To better understand the influences of this genomic region, the congenic rat strain SLA16 (SHR.LEW-Anxrr16) was developed. SLA16 rats present higher hyperactivity/impulsivity, deficits in learning and memory, and lower basal blood pressure than the SHR strain, even though genetic differences between them are only in chromosome 4. Thus, the present study proposed the alpha-synuclein and the dopaminergic system as candidates to explain the differential behavior of SHR and SLA16 strains. To accomplish this, beyond the behavioral analysis, we performed (I) the Snca gene expression and (II) quantification of the alpha-synuclein protein in the hippocampus (HPC), prefrontal cortex (PFC), and striatum (STR) of SHR and SLA16 strains; (III) sequencing of the 3'UTR of the Snca gene; and (IV) evaluation of miRNA binding in the 3'UTR site. A Single Nucleotide Polymorphism (SNP) was identified in the 3'UTR of the Snca gene, which exhibited upregulation in the HPC of SHR compared to SLA16 females. Alpha-synuclein protein was higher in the HPC of SHR males compared to SLA16 males. The results of this work suggested that differences in alpha-synuclein HPC content could be influenced by miRNA regulation and associated with behavioral differences between SHR and SLA16 animals.

SKOR1 has a transcriptional regulatory role on genes involved in pathways related to restless legs syndrome.

Restless legs syndrome (RLS) is a common sleep-related sensory-motor disorder. It is characterized by uncomfortable sensations in the legs during the evening or at night. The symptoms can be partially relieved by movement, so typically affected individual needs to walk during rest time; this interferes with sleep. GWAS have identified 19 RLS-associated loci. Among the first to be reported and most significant and robustly replicated reports are variants in the SKOR1 noncoding regions. SKOR1 is highly expressed in the CNS of humans and mice. Skor1 acts as a corepressor of Lbx1 transcription factor in mice and these two genes act together to regulate the cell fate of interneurons in the dorsal horn of the spinal cord. Based on this data we investigated the regulatory role of SKOR1 using a global RNA-sequencing approach in human cell lines where SKOR1 was either overexpressed or silenced. For this work we generated and validated a new poly-clonal anti-SKOR1. Pathway and gene set enrichment analyses of the differentially expressed genes showed, among others, enrichment of genes involved in neurodevelopment and iron metabolism, two RLS relevant pathways that were previously found to be enriched in the latest RLS GWAS meta-analysis. Analysis of our different datasets further supports and highlights the regulatory role of SKOR1, which when dysregulated might represent a key pathogenic element of RLS. A better understanding of SKOR1 and its activity could open new avenues of investigation for the development of a much-needed therapy.

Genetic and epidemiological characterization of restless legs syndrome in Québec.

Currently, a total of 19 genetic loci are associated with the risk for developing RLS. This study aimed to assess these RLS predisposing genetic variants, as well as investigate the epidemiological profile and diagnostic features of individuals with RLS in the Québec population, using an interviewer-administered questionnaire. A total of 18 RLS-associated variants were genotyped in the Québec population-based CARTaGENE cohort. A case-control series consisting of 1,362 RLS cases and 1,379 age-matched unaffected controls was used to conduct a genetic and epidemiological association study that integrated the first four RLS diagnostic features of affected individuals, as well as additional RLS-related questions (e.g. frequency of the symptoms and number of total pregnancies in female). Five RLS-predisposing variants were significantly associated after Bonferroni correction and an additional five variants were nominally associated with RLS (p < 0.05). BTBD9 was the strongest genetic risk factor in our cohort (rs9296249, OR = 1.71, p = 9.57 × 10-10). The patient group that met all four essential diagnostic criteria of RLS provided the most significant genetic findings. These results suggest that employing the questionnaire which included standard diagnostic criteria of RLS could improve the accuracy of the survey-based studies.