Global phylogeography of yellowfin tuna, Thunnus albacares, and mackerels of the genus Scomber

Intraspecific genetic relationships within yellowfin tuna, Thunnus albacares, and three mackerels of the genus Scomber were studied by restriction fragment length polymorphism (RFLP) analysis of mitochondrial DNA (mtDNA). The comparison of these scombrids, with different larval distributions, adult distributions, and vagilities, served to investigate the hypothesis that population structure in marine fishes results from geographic and physical oceanographic processes that limit dispersal of early life history stages. Samples of 20 yellowfin tuna were examined from each of five Pacific locations and one Atlantic location. MtDNA analysis with 12 informative restriction endonucleases demonstrated considerable genetic variation, as evidenced by overall nucleon diversity of 0.84 and mean nucleotide sequence diversity of 0.31%. Estimates of within-sample variation were consistent across all six locations. Common genotypes occurred with similar frequencies in all samples, and with one exception, all genotypes that were represented by more than one individual occurred at more than one location. The null hypothesis that the sampled populations of yellowfin tuna share a common gene pool was not rejected. In contrast, analysis of species of Scomber revealed considerable intraspecific differentiation. A total of 15 samples averaging 19 individuals each of Scomber japonicus, S. australasicus, and S. scombrus were collected from geographically isolated populations throughout the ranges of each species. Genotypic diversities ranged from 0.28 to 0.95, and nucleotide sequence diversities from 0.13 to 0.76%. East and west Atlantic populations of S. scombrus exhibited significant differentiation, but no fixed restriction site differences. This species differed by 11.9% nucleotide sequence divergence from the other two species. In S. japonicus, fixed restriction site differences were revealed among Pacific samples, but not among Atlantic samples; although significant heterogeneity occurred within the Atlantic. In S. australasicus, North and South Pacific samples were highly differentiated. One of two divergent mtDNA matrilines observed in this species was restricted to southern samples. The study demonstrated that population structure is greater in the species of Scomber than in yellowfin tuna. It further revealed that adult dispersal, in addition to geographic and physical oceanographic processes that control dispersal of early life history stages, are of significant importance in shaping population structure in scombrids

The autosomal recessive juvenile Parkinson disease gene product, parkin, interacts with and ubiquitinates synaptotagmin XI.

Inactivating mutations of the gene encoding parkin are responsible for some forms of autosomal recessive juvenile Parkinson disease. Parkin is a ubiquitin ligase that ubiquitinates misfolded proteins targeted for the proteasome-dependent protein degradation pathway. Using the yeast two-hybrid system and coimmunoprecipitation methods, we identified synaptotagmin XI as a protein that interacts with parkin. Parkin binds to the C2A and C2B domains of synaptotagmin XI resulting in the polyubiquitination of synaptotagmin XI. Truncated and missense mutated parkins reduce parkin-sytXI binding affinity and ubiquitination. Parkinmediated ubiquitination also enhances the turnover of sytXI. In sporadic PD brain sections, sytXI was found in the core of the Lewy bodies. Since synaptotagmin XI is a member of the synaptotagmin family that is well characterized in their importance for vesicle formation and docking, the interaction with this protein suggests a role for parkin in the regulation of the synaptic vesicle pool and in vesicle release. Loss of parkin could thus affect multiple proteins controlling vesicle pools, docking and release and explain the deficits in dopaminergic function seen in patients with parkin mutations

Androgen receptor cytosine-adenine-guanine repeat polymorphisms modulate EGFR signaling in epithelial ovarian carcinomas

Abstract Objective. Length of a polymorphic cytosine-adenine-guanine (CAG) repeat in the androgen receptor (AR) may inversely correlate with AR activity. We have identified an association between short AR allelotypes and decreased survival in women with epithelial ovarian cancer. We hypothesize short AR allelotypes promote aggressive ovarian cancer phenotype through modulation of epidermal growth factor receptor (EGFR) signaling. Methods. SKOV-3 cells were transfected with AR plasmids containing variable CAG repeat lengths, and AR activity was assessed through cotransfection with a luciferase plasmid. EGFR signaling was studied with Western blot analysis of EGFR, EGFR-p (phosphorylated), MAPK, and MAPK-p, and cellular proliferation examined by MTT assays. Data were analyzed using analysis of variance, Tukey-Kramer multiple comparison test, and Student's t test. Results. We confirmed AR allelotype length inversely correlates with AR activity in epithelial ovarian cells; a 2.5% decrease in luciferase-fold activation was seen with each CAG unit increase ( p = 0.0002). We observed inhibition of EGFR-p abundance with increasing abundance of transfected AR cDNA (89.2% and 39.9% for 3.0 and 6.0 μg, compared to 1.5 μg, p = 0.03). After transfection with short (CAG = 14), median (CAG = 21), and long (CAG = 24) AR allelotypes, an inverse correlation was identified between abundance of MAPK-p and CAG repeat length ( p = 0.002). Decrease in cellular abundance was also seen in cultures transfected with ARs of increasing CAG repeat length ( p b 0.0001). Conclusions. These data identify an inhibitory action of AR on EGFR signaling, and support research investigating AR/EGFR antagonism in the treatment of ovarian cancers

Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in spinocerebellar ataxia type 1

Selective neuronal vulnerability in neurodegenerative disease is poorly understood. Using the ATXN1[82Q] model of spinocerebellar ataxia type 1 (SCA1), we explored the hypothesis that regional differences in Purkinje neuron degeneration could provide novel insights into selective vulnerability. ATXN1[82Q] Purkinje neurons from the anterior cerebellum were found to degenerate earlier than those from the nodular zone, and this early degeneration was associated with selective dysregulation of ion channel transcripts and altered Purkinje neuron spiking. Efforts to understand the basis for selective dysregulation of channel transcripts revealed modestly increased expression of the ATXN1 co-repressor Capicua (Cic) in anterior cerebellar Purkinje neurons. Importantly, disrupting the association between ATXN1 and Cic rescued the levels of these ion channel transcripts, and lentiviral overexpression of Cic in the nodular zone accelerated both aberrant Purkinje neuron spiking and neurodegeneration. These findings reinforce the central role for Cic in SCA1 cerebellar pathophysiology and suggest that only modest reductions in Cic are needed to have profound therapeutic impact in SCA1

Profiling allele-specific gene expression in brains from individuals with autism spectrum disorder reveals preferential minor allele usage.

One fundamental but understudied mechanism of gene regulation in disease is allele-specific expression (ASE), the preferential expression of one allele. We leveraged RNA-sequencing data from human brain to assess ASE in autism spectrum disorder (ASD). When ASE is observed in ASD, the allele with lower population frequency (minor allele) is preferentially more highly expressed than the major allele, opposite to the canonical pattern. Importantly, genes showing ASE in ASD are enriched in those downregulated in ASD postmortem brains and in genes harboring de novo mutations in ASD. Two regions, 14q32 and 15q11, containing all known orphan C/D box small nucleolar RNAs (snoRNAs), are particularly enriched in shifts to higher minor allele expression. We demonstrate that this allele shifting enhances snoRNA-targeted splicing changes in ASD-related target genes in idiopathic ASD and 15q11-q13 duplication syndrome. Together, these results implicate allelic imbalance and dysregulation of orphan C/D box snoRNAs in ASD pathogenesis

MTSS1/Src family kinase Dysregulation Underlies Multiple Inherited Ataxias

The genetically heterogeneous spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of nonreceptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-metastasis (MTSS1) is an ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically approved Src inhibitor corrects Purkinje neuron basal firing and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression

Molecular dynamics analysis of the aggregation propensity of polyglutamine segments.

Protein misfolding and aggregation is a pathogenic feature shared among at least ten polyglutamine (polyQ) neurodegenerative diseases. While solvent-solution interaction is a key factor driving protein folding and aggregation, the solvation properties of expanded polyQ tracts are not well understood. By using GPU-enabled all-atom molecular dynamics simulations of polyQ monomers in an explicit solvent environment, this study shows that solvent-polyQ interaction propensity decreases as the lengths of polyQ tract increases. This study finds a predominance in long-distance interactions between residues far apart in polyQ sequences with longer polyQ segments, that leads to significant conformational differences. This study also indicates that large loops, comprised of parallel β-structures, appear in long polyQ tracts and present new aggregation building blocks with aggregation driven by long-distance intra-polyQ interactions. Finally, consistent with previous observations using coarse-grain simulations, this study demonstrates that there is a gain in the aggregation propensity with increased polyQ length, and that this gain is correlated with decreasing ability of solvent-polyQ interaction. These results suggest the modulation of solvent-polyQ interactions as a possible therapeutic strategy for treating polyQ diseases

Solvent-polyQ hydrogen bond count at the atomic level.

<p><b>A</b>. Total count. <b>B</b>. Count normalized by polyQ length. Shapes indicate hydrogen bonds of different donor and acceptor types. The error bars represent the standard deviation of the average values calculated over the six independent MD runs performed in this study.</p