SNPs in SNCA,MCCC1, DLG2, GBF1 and MBNL2 are associated with Parkinson's disease in southern Chinese population

Numerous single nucleotide polymorphisms (SNPs), which have been identified as susceptibility factors for Parkinson's disease (PD) as per genome‐wide association studies, have not been fully characterized for PD patients in China. This study aimed to replicate the relationship between 12 novel SNPs of 12 genes and PD risk in southern Chinese population. Twelve SNPs of 12 genes were detected in 231 PD patients and 249 controls, using the SNaPshot technique. Meta‐analysis was used to assess heterogeneity of effect sizes between this study and published data. The impact of SNPs on gene expression was investigated by analysing the SNP‐gene association in the expression quantitative trait loci (eQTL) data sets. rs8180209 of SNCA (allele model: P = .047, OR = 0.77; additive model: P = .047, OR = 0.77), rs2270968 of MCCC1 (dominant model: P = .024, OR = 1.52), rs7479949 of DLG2 (recessive model; P = .019, OR = 1.52), rs10748818 of GBF1 (additive model: P < .001, OR = 0.37), and rs4771268 of MBNL2 (recessive model: P = .003, OR = 0.48) were replicated to be significantly associated with the increased risk of PD. Noteworthy, a meta‐analysis of previous studies suggested rs8180209, rs2270968, rs7479949 and rs4771268 were in line with those of our cohort. Our study replicated five novel functional SNPs in SNCA, MCCC1, DLG2, GBF1 and MBNL2 could be associated with increased risk of PD in southern Chinese population.     

Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson's disease

Intra‐neuronal metabolism of dopamine (DA) begins with production of 3,4‐dihydroxyphenylacetaldehyde (DOPAL), which is toxic. According to the ‘catecholaldehyde hypothesis,’ DOPAL destroys nigrostriatal DA terminals and contributes to the profound putamen DA deficiency that characterizes Parkinson's disease (PD). We tested the feasibility of using post‐mortem patterns of putamen tissue catechols to examine contributions of altered activities of the type 2 vesicular monoamine transporter (VMAT2) and aldehyde dehydrogenase (ALDH) to the increased DOPAL levels found in PD. Theoretically, the DA : DOPA concentration ratio indicates vesicular uptake, and the 3,4‐dihydroxyphenylacetic acid : DOPAL ratio indicates ALDH activity. We validated these indices in transgenic mice with very low vesicular uptake (VMAT2‐Lo) or with knockouts of the genes encoding ALDH1A1 and ALDH2 (ALDH1A1,2 KO), applied these indices in PD putamen, and estimated the percent decreases in vesicular uptake and ALDH activity in PD. VMAT2‐Lo mice had markedly decreased DA:DOPA (50 vs. 1377, p < 0.0001), and ALDH1A1,2 KO mice had decreased 3,4‐dihydroxyphenylacetic acid:DOPAL (1.0 vs. 11.2, p < 0.0001). In PD putamen, vesicular uptake was estimated to be decreased by 89% and ALDH activity by 70%. Elevated DOPAL levels in PD putamen reflect a combination of decreased vesicular uptake of cytosolic DA and decreased DOPAL detoxification by ALDH.

     

Pen‐2 is dispensable for endoproteolysis of presenilin 1, and nicastrin‐Aph subcomplex is important for both γ‐secretase assembly and substrate recruitment

γ‐secretase is a protease complex with at least four components: presenilin, nicastrin (NCT), anterior pharynx‐defective 1 (Aph‐1), and presenilin enhancer 2 (Pen‐2). In this study, using knockout cell lines and small interfering RNA technology, our data demonstrated that the disappeared presenilin 1 C‐terminal fragment (PS1C) caused by knockdown of pen‐2 or knockout of NCT or Aph‐1 was recovered by the addition of proteasome inhibitors, indicating that Pen‐2, as well as NCT and Aph‐1α, is dispensable for presenilin endoproteolysis. Our data also demonstrate that the formation of the nicastrin‐Aph‐1 subcomplex plays not only an important role in γ‐secretase complex assembly but also in recruiting substrate C‐terminal fragment of amyloid precursor protein generated by β‐cleavage. Ablating any one component resulted in the instability of other components of the γ‐secretase complex, and the presence of all three of the other components is required for full maturation of NCT.     

Termite mounds alter the spatial distribution of African savanna tree species: artefacts and real patterns

In a recent issue (vol. 43) of the Journal of Biogeography, Davies et al. (2015) presented novel analyses of the spatial distribution of tree species around termite mounds in a South African savanna. However, some of their conclusions are not supported by the data. My aim in this correspondence is to point out some limitations of their analyses, stimulate cautious interpretation of their results and suggest better methods for future use.     

A metabolic signature for long life in the Caenorhabditis elegans Mit mutants

Mit mutations that disrupt function of the mitochondrial electron transport chain can, inexplicably, prolong Caenorhabditis elegans lifespan. In this study we use a metabolomics approach to identify an ensemble of mitochondrial‐derived α‐ketoacids and α‐hydroxyacids that are produced by long‐lived Mit mutants but not by other long‐lived mutants or by short‐lived mitochondrial mutants. We show that accumulation of these compounds is dependent on concerted inhibition of three α‐ketoacid dehydrogenases that share dihydrolipoamide dehydrogenase (DLD) as a common subunit, a protein previously linked in humans with increased risk of Alzheimer's disease. When the expression of DLD in wild‐type animals was reduced using RNA interference we observed an unprecedented effect on lifespan – as RNAi dosage was increased lifespan was significantly shortened, but, at higher doses, it was significantly lengthened, suggesting that DLD plays a unique role in modulating length of life. Our findings provide novel insight into the origin of the Mit phenotype.     

Pantoea stewartii Causing Stewart's Wilt on Dracaena sanderiana in Korea

In April 2010, a severe occurrence of Stewart's wilt on Dracaena sanderiana plants was observed in greenhouses in Seongnam, Gyeonggi Province, South Korea, with an incidence of 35‐50%. Being imported plants, little was known about the pathogens associated with D. sanderiana. Symptoms included chlorosis, wilting and leaf blight on the leaf surfaces. Physiological analysis, pathogenicity tests, sequencing and phylogenetic analysis of the 16S rRNA gene revealed that the pathogen was the bacterium Pantoea stewartii. To the best of our knowledge, this is the first report on bacterial wilt caused by P. stewartii on D. sanderiana.     

Progressive brain metabolic changes under deep brain stimulation of subthalamic nucleus in parkinsonian rats

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an efficient neurosurgical treatment for advanced Parkinson's disease. Non‐invasive metabolic neuroimaging during the course of DBS in animal models may contribute to our understanding of its action mechanisms. Here, DBS was adapted to in vivo proton magnetic resonance spectroscopy at 11.7 T in the rat to follow metabolic changes in main basal ganglia structures, the striatum, and the substantia nigra pars reticulata (SNr). Measurements were repeated OFF and ON acute and subchronic (7 days) STN‐DBS in control and parkinsonian (6‐hydroxydopamine lesion) conditions. Acute DBS reversed the increases in glutamate, glutamine, and GABA levels induced by the dopamine lesion in the striatum but not in the SNr. Subchronic DBS normalized GABA in both the striatum and SNr, and glutamate in the striatum. Taurine levels were markedly decreased under subchronic DBS in the striatum and SNr in both lesioned and unlesioned rats. Microdialysis in the striatum further showed that extracellular taurine was increased. These data reveal that STN‐DBS has duration‐dependent metabolic effects in the basal ganglia, consistent with development of adaptive mechanisms. In addition to counteracting defects induced by the dopamine lesion, prolonged DBS has proper effects independent of the pathological condition.

     

Loss of Bace2 in zebrafish affects melanocyte migration and is distinct from Bace1 knock out phenotypes

Alzheimer's disease is the most frequent dementia. Pathologically, Alzheimer's disease is characterized by the accumulation of senile plaques composed of amyloid β‐peptide (Aβ). Two proteases, β‐ and γ‐secretase proteolytically generate Aβ from its precursor, the ß‐amyloid precursor protein (APP). Inhibition of β‐secretase, also referred to as b eta‐site A PP c leaving e nzyme (BACE1) or γ‐secretase is therefore of prime interest for the development of amyloid‐lowering drugs. To assess the in vivo function of zebrafish Bace1 (zBace1), we generated zBace1 knock out fish by zinc finger nuclease‐mediated genome editing. bace1 mutants (bace1?/?) are hypomyelinated in the PNS while the CNS is not affected. Moreover, the number of mechanosensory neuromasts is elevated in bace1?/?. Mutations in zebrafish Bace2 (zBace2) revealed a distinct melanocyte migration phenotype, which is not observed in bace1?/?. Double homozygous bace1?/?; bace2?/? fish do not enhance the single mutant phenotypes indicating non‐redundant distinct physiological functions. Single homozygous bace1 mutants as well as double homozygous bace1 and bace2 mutants are viable and fertile suggesting that Bace1 is a promising drug target without major side effects. The identification of a specific bace2 ?/? associated phenotype further allows improving selective Bace1 inhibitors and to distinguish between Bace 1 and Bace 2 inhibition in vivo.

     

Sperm competitive advantage of a rare mitochondrial haplogroup linked to differential expression of mitochondrial oxidative phosphorylation genes

Maternal inheritance of mitochondria creates a sex‐specific selective sieve through which mitochondrial mutations harmful to males but not females accumulate and contribute to sexual differences in longevity and disease susceptibility. Because eggs and sperm are under disruptive selection, sperm are predicted to be particularly vulnerable to the genetic load generated by maternal inheritance, yet evidence for mitochondrial involvement in male fertility is limited and controversial. Here, we exploit the coexistence of two divergent mitochondrial haplogroups (A and B2) in a Neotropical arachnid to investigate the role of mitochondria in sperm competition. DNA profiling demonstrated that B2‐carrying males sired more than three times as many offspring in sperm competition experiments than A males, and this B2 competitive advantage cannot be explained by female mitochondrial haplogroup or male nuclear genetic background. RNA‐Seq of testicular tissues implicates differential expression of mitochondrial oxidative phosphorylation (OXPHOS) genes in the B2 competitive advantage, including a 22‐fold upregulation of atp8 in B2 males. Previous comparative genomic analyses have revealed functionally significant amino acid substitutions in differentially expressed genes, indicating that the mitochondrial haplogroups differ not only in expression but also in DNA sequence and protein functioning. However, mitochondrial haplogroup had no effect on sperm number or sperm viability, and, when females were mated to a single male, neither male haplogroup, female haplogroup nor the interaction between male/female haplogroup significantly affected female reproductive success. Our findings therefore suggest that mitochondrial effects on male reproduction may often go undetected in noncompetitive contexts and may prove more important in nature than is currently appreciated.     

Description and identification of two new diseases of guariroba palm (Syagrus oleraceae) in Brazil

Guariroba is a palm species native to central Brazil. Seedlings of guariroba with leaf spots of unknown aetiology were found in Patos de Minas, Minas Gerais, Brazil. The leaf spots were manifest as two different symptom types: the first lesion type consisted of necrotic spots with a rounded to elongate shape, with a light colour and dark edges; the second lesion type had a rounded shape, was dark brown in colour with a light brown edge. The objective of this study was to elucidate the aetiology of both diseases. The likely causal agents were isolated and Koch's postulate fulfilled. Subsequently, the ITS region of rDNA from both micro‐organisms were amplified and sequenced. According to the morphological characteristics and molecular analyses, the fungal species were identified as Pestalotiopsis adusta (causing necrotic spots with a rounded to elongate shape, with a light colour and dark edges), and Alternaria tenuissima (causing lesions with a rounded shape, dark brown in colour with a light brown edge). Identification of the causal organisms of these two diseases will help guide management approaches that might be tested to reduce impact of the disease on Guariroba, including the use of fungicides and cultural approaches.     

A further cost for the sicker sex? Evidence for male‐biased parasite‐induced vulnerability to predation

Males are typically the sicker sex. Data from multiple taxa indicate that they are more likely to be infected with parasites, and are less “tolerant,” or less able to mitigate the fitness costs of a given infection, than females. One cost of infection for many animals is an increased probability of being captured by a predator. A clear, hitherto untested, prediction is therefore that this parasite‐induced vulnerability to predation is more pronounced among males than females. We tested this prediction in the sexually size dimorphic guppy, Poecilia reticulata, in which females are typically larger than males. We either sham or experimentally infected guppies with Gyrodactylus turnbulli, elicited their escape response using an established protocol and measured the distance they covered during 60 ms. To discriminate between the effects of body size and those of other inherent sex differences, we size‐matched fish across treatment groups. Infection with G. turnbulli reduced the distance covered during the escape response of small adults by 20.1%, whereas that of large fish was unaffected. This result implies that parasite‐induced vulnerability to predation is male‐biased in the wild: although there was no difference in escape response between our experimentally size‐matched groups of males and females, males are significantly smaller across natural guppy populations. These results are consistent with Bateman's principle for immunity: Natural selection for larger body sizes and longevity in females seems to have resulted in the evolution of increased infection tolerance. We discuss the potential implications of sex‐ and size‐biased parasite‐induced vulnerability to predation for the evolutionary ecology of this host–parasite interaction in natural communities.