共查询到20条相似文献,搜索用时 15 毫秒
1.
Simone Poddighe Krishna Moorthi Bhat Maria Dolores Setzu Paolo Solla Anna Maria Angioy Roberto Marotta Roberta Ruffilli Francesco Marrosu Anna Liscia 《PloS one》2013,8(8)
Parkinson’s disease (PD) is one of the most common neurodegenerative disease characterized by the clinical triad: tremor, akinesia and rigidity. Several studies have suggested that PD patients show disturbances in olfaction at the earliest onset of the disease. The fruit fly Drosophila melanogaster is becoming a powerful model organism to study neurodegenerative diseases. We sought to use this system to explore olfactory dysfunction, if any, in PINK1 mutants, which is a model for PD. PINK1 mutants display many important diagnostic symptoms of the disease such as akinetic motor behavior. In the present study, we describe for the first time, to the best of our knowledge, neurophysiological and neuroanatomical results concerning the olfactory function in PINK1 mutant flies. Electroantennograms were recorded in response to synthetic and natural volatiles (essential oils) from groups of PINK1 mutant adults at three different time points in their life cycle: one from 3–5 day-old flies, from 15–20 and from 27–30 days. The results obtained were compared with the same age-groups of wild type flies. We found that mutant adults showed a decrease in the olfactory response to 1-hexanol, α-pinene and essential oil volatiles. This olfactory response in mutant adults decreased even more as the flies aged. Immunohistological analysis of the antennal lobes in these mutants revealed structural abnormalities, especially in the expression of Bruchpilot protein, a marker for synaptic active zones. The combination of electrophysiological and morphological results suggests that the altered synaptic organization may be due to a neurodegenerative process. Our results indicate that this model can be used as a tool for understanding PD pathogensis and pathophysiology. These results help to explore the potential of using olfaction as a means of monitoring PD progression and developing new treatments. 相似文献
2.
Siddhita D. Mhatre Vivek Satyasi Mark Killen Brie E. Paddock Robert D. Moir Aleister J. Saunders Daniel R. Marenda 《Disease models & mechanisms》2014,7(3):373-385
Alzheimer’s disease (AD) is an age-related neurodegenerative disease characterized by memory loss and decreased synaptic function. Advances in transgenic animal models of AD have facilitated our understanding of this disorder, and have aided in the development, speed and efficiency of testing potential therapeutics. Recently, we have described the characterization of a novel model of AD in the fruit fly, Drosophila melanogaster, where we expressed the human AD-associated proteins APP and BACE in the central nervous system of the fly. Here we describe synaptic defects in the larval neuromuscular junction (NMJ) in this model. Our results indicate that expression of human APP and BACE at the larval NMJ leads to defective larval locomotion behavior, decreased presynaptic connections, altered mitochondrial localization in presynaptic motor neurons and decreased postsynaptic protein levels. Treating larvae expressing APP and BACE with the γ-secretase inhibitor L-685,458 suppresses the behavioral defects as well as the pre- and postsynaptic defects. We suggest that this model will be useful to assess and model the synaptic dysfunction normally associated with AD, and will also serve as a powerful in vivo tool for rapid testing of potential therapeutics for AD.KEY WORDS: APP, Alzheimer’s disease, Drosophila, BACE, Synapse, NMJ 相似文献
3.
Arthur L. Caplan 《PLoS biology》2015,13(8)
Since the early 1970s, the ethical norm governing counselors involved in testing and screening for genetic conditions related to reproduction has been strict neutrality. Counseling about reproductive genetics was to be patient centered but nondirective. Many advocates for people with Down syndrome believe that high abortion rates following a diagnosis of this condition show an unfounded bias against those with Down syndrome. These advocates have succeeded in enacting federal and state legislation that requires women who receive a prenatal diagnosis of Down syndrome to receive positive information about the condition, thereby ending the nominal goal of value-neutral counseling and setting the stage for further normative shifts in clinical reproductive genetics as counseling expands because of cell-free testing.
This Perspective is part of the “Where Next?” Series.相似文献
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Three-year-old children were observed in two free-play sessions and participated in a toy-retrieval task, in which only one
of six tools could be used to retrieve an out-of-reach toy. Boys engaged in more object-oriented play than girls and were
more likely to use tools to retrieve the toy during the baseline tool-use task. All children who did not retrieve the toy
during the baseline trials did so after being given a hint, and performance on a transfer-of-training tool-use task approached
ceiling levels. This suggests that the sex difference in tool use observed during the baseline phase does not reflect a difference
in competency, but rather a sex difference in motivation to interact with objects. Amount of time boys, but not girls, spent
in object-oriented play during the free-play sessions predicted performance on the tool-use task. The findings are interpreted
in terms of evolutionary theory, consistent with the idea that boys’ and girls’ play styles evolved to prepare them for adult
life in traditional environments. 相似文献
6.
Naser Poursarebani Tina Seidensticker Ravi Koppolu Corinna Trautewig Piotr Gawroński Federica Bini Geetha Govind Twan Rutten Shun Sakuma Akemi Tagiri Gizaw M. Wolde Helmy M. Youssef Abdulhamit Battal Stefano Ciannamea Tiziana Fusca Thomas Nussbaumer Carlo Pozzi Andreas B?rner Udda Lundqvist Takao Komatsuda Silvio Salvi Roberto Tuberosa Cristobal Uauy Nese Sreenivasulu Laura Rossini Thorsten Schnurbusch 《Genetics》2015,201(1):155-165
7.
Despite being a paradigm of quantitative linguistics, Zipf’s law for words suffers from three main problems: its formulation is ambiguous, its validity has not been tested rigorously from a statistical point of view, and it has not been confronted to a representatively large number of texts. So, we can summarize the current support of Zipf’s law in texts as anecdotic. We try to solve these issues by studying three different versions of Zipf’s law and fitting them to all available English texts in the Project Gutenberg database (consisting of more than 30 000 texts). To do so we use state-of-the art tools in fitting and goodness-of-fit tests, carefully tailored to the peculiarities of text statistics. Remarkably, one of the three versions of Zipf’s law, consisting of a pure power-law form in the complementary cumulative distribution function of word frequencies, is able to fit more than 40% of the texts in the database (at the 0.05 significance level), for the whole domain of frequencies (from 1 to the maximum value), and with only one free parameter (the exponent). 相似文献
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It is hypothesized from within an evolutionary framework that females should be less invested in peer relations than males. Investment was operationalized as enjoyment in Study 1 and as preference for interaction in Study 2. In the first study, four- and six-year-old children’s enjoyment of peer interaction was observed in 26 groups of same-sex peers. Girls were rated as enjoying their interactions significantly less than boys. In the second study, six- and nine-year-old children were interviewed about the individuals with whom they spend time in their homes and neighborhoods and about the individuals who participate in their favorite activities. The proportion of individuals named by children who were peers was significantly lower for girls than boys both in children’s neighborhoods and in children’s favorite activities. Results strongly support the hypothesis that females and males have evolved differential preferences for interaction with peers. 相似文献
10.
The past 25 years have seen significant advances in understanding the diversity and functions of glycoprotein glycans in Drosophila melanogaster. Genetic screens have captured mutations that reveal important biological activities modulated by glycans, including protein folding and trafficking, as well as cell signaling, tissue morphogenesis, fertility, and viability. Many of these glycan functions have parallels in vertebrate development and disease, providing increasing opportunities to dissect pathologic mechanisms using Drosophila genetics. Advances in the sensitivity of structural analytic techniques have allowed the glycan profiles of wild-type and mutant tissues to be assessed, revealing novel glycan structures that may be functionally analogous to vertebrate glycans. This review describes a selected set of recent advances in understanding the functions of N-linked and O-linked (non-glycosaminoglycan) glycoprotein glycans in Drosophila with emphasis on their relatedness to vertebrate organisms. 相似文献
11.
Yih-Ru Wu Kuo-Hsuan Chang Wen-Teng Chang Ya-Chin Hsiao Hsuan-Chu Hsu Pei-Ru Jiang Yi-Chun Chen Chih-Ying Chao Yi-Chung Chang Bo-Hsun Lee Fen-Ju Hu Wan-Ling Chen Guey-Jen Lee-Chen Chiung-Mei Chen 《PloS one》2013,8(12)
Genetic variants of leucine-rich repeat kinase 2 (LRRK2) were reported to alter the risk for Parkinson’s disease (PD). However, the genetic spectrum of LRRK2 variants has not been clearly disclosed yet in Taiwanese population. Herein, we sequenced LRRK2 coding region in 70 Taiwanese early onset PD patients (age at onset ≤ 50), and found six amino acid-changing single nucleotide polymorphisms (SNPs, N551K, R1398H, R1628P, S1647T, G2385R and M2397T), one reported (R1441H) and 2 novel missense (R767H and S885N) mutations. We examined the frequency of identified LRRK2 variants by genotyping 573 Taiwanese patients with PD and 503 age-matched control subjects. The results showed that PD patients demonstrated a higher frequency of G2385R A allele (4.6%) than control subjects (2.1%; odds ratio = 2.27, 95% confidence interval: 1.38–3.88, P = 0.0017). Fewer PD patients (27.7%) carried the 1647T-2397T haplotype as compared with the control subjects (33.0%; odds ratio = 0.80, 95% confidence interval: 0.65–0.97, P = 0.0215). However, the frequency of 1647T-2385R-2397T haplotype (4.3%) in PD patients was still higher than in control subjects (1.9%, odds ratio: 2.15, 95% confidence interval: 1.27–3.78, P = 0.0058). While no additional subject was found to carry R767H and R1441H, one more patient was observed to carry the S885N variant. Our results indicate a robust risk association regarding G2385R and a new possible protective haplotype (1647T-2397T). Gene-environmental interaction and a larger cohort study are warranted to validate our findings. Additionally, two new missense mutations (R767H and S885N) regarding LRRK2 in PD patients were identified. Functional studies are needed to elucidate the effects of these LRRK2 variants on protein function. 相似文献
12.
Erin N Smith Kristen Jepsen Angelo D Arias Peter J Shepard Christina D Chambers Kelly A Frazer 《Genome biology》2014,15(2):1-7
Background
The National Children’s Study (NCS) is a prospective epidemiological study in the USA tasked with identifying a nationally representative sample of 100,000 children, and following them from their gestation until they are 21 years of age. The objective of the study is to measure environmental and genetic influences on growth, development, and health. Determination of the ancestry of these NCS participants is important for assessing the diversity of study participants and for examining the effect of ancestry on various health outcomes.Results
We estimated the genetic ancestry of a convenience sample of 641 parents enrolled at the 7 original NCS Vanguard sites, by analyzing 30,000 markers on exome arrays, using the 1000 Genomes Project superpopulations as reference populations, and compared this with the measures of self-reported ethnicity and race. For 99% of the individuals, self-reported ethnicity and race agreed with the predicted superpopulation. NCS individuals self-reporting as Asian had genetic ancestry of either South Asian or East Asian groups, while those reporting as either Hispanic White or Hispanic Other had similar genetic ancestry. Of the 33 individuals who self-reported as Multiracial or Non-Hispanic Other, 33% matched the South Asian or East Asian groups, while these groups represented only 4.4% of the other reported categories.Conclusions
Our data suggest that self-reported ethnicity and race have some limitations in accurately capturing Hispanic and South Asian populations. Overall, however, our data indicate that despite the complexity of the US population, individuals know their ancestral origins, and that self-reported ethnicity and race is a reliable indicator of genetic ancestry. 相似文献13.
Bashayer R. Al-Mubarak Saeed A. Bohlega Thamer S. Alkhairallah Amna I. Magrashi Maha I. AlTurki Dania S. Khalil Basma S. AlAbdulaziz Hussam Abou Al-Shaar Abeer E. Mustafa Eman A. Alyemni Bashayer A. Alsaffar Asma I. Tahir Nada A. Al Tassan 《PloS one》2015,10(8)
Parkinson’s disease (PD) is one of the major causes of parkinsonism syndrome. Its characteristic motor symptoms are attributable to dopaminergic neurons loss in the midbrain. Genetic advances have highlighted underlying molecular mechanisms and provided clues to potential therapies. However, most of the studies focusing on the genetic component of PD have been performed on American, European and Asian populations, whereas Arab populations (excluding North African Arabs), particularly Saudis remain to be explored. Here we investigated the genetic causes of PD in Saudis by recruiting 98 PD-cases (sporadic and familial) and screening them for potential pathogenic mutations in PD-established genes; SNCA, PARKIN, PINK1, PARK7/DJ1, LRRK2 and other PD-associated genes using direct sequencing. To our surprise, the screening revealed only three pathogenic point mutations; two in PINK1 and one in PARKIN. In addition to mutational analysis, CNV and cDNA analysis was performed on a subset of patients. Exon/intron dosage alterations in PARKIN were detected and confirmed in 2 cases. Our study suggests that mutations in the ORF of the screened genes are not a common cause of PD in Saudi population; however, these findings by no means exclude the possibility that other genetic events such as gene expression/dosage alteration may be more common nor does it eliminate the possibility of the involvement of novel genes. 相似文献
14.
Ko-Fan Chen Bernard Possidente David A. Lomas Damian C. Crowther 《Disease models & mechanisms》2014,7(4):445-458
Circadian behavioural deficits, including sleep irregularity and restlessness in the evening, are a distressing early feature of Alzheimer’s disease (AD). We have investigated these phenomena by studying the circadian behaviour of transgenic Drosophila expressing the amyloid beta peptide (Aβ). We find that Aβ expression results in an age-related loss of circadian behavioural rhythms despite ongoing normal molecular oscillations in the central clock neurons. Even in the absence of any behavioural correlate, the synchronised activity of the central clock remains protective, prolonging lifespan, in Aβ flies just as it does in control flies. Confocal microscopy and bioluminescence measurements point to processes downstream of the molecular clock as the main site of Aβ toxicity. In addition, there seems to be significant non-cell-autonomous Aβ toxicity resulting in morphological and probably functional signalling deficits in central clock neurons.KEY WORDS: Alzheimer’s disease, Circadian dysfunction, Non-cell-autonomous Aβ toxicity, Drosophila model, Biological clock 相似文献
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Cryptic evolution has been defined as adaptive evolutionary change being masked by concurrent environmental change. Empirical studies of cryptic evolution have usually invoked a changing climate and/or increasing population density as the form of detrimental environmental change experienced by a population undergoing cryptic evolution. However, Fisher (1958) emphasized that evolutionary change in itself is likely to be an important component of "environmental deterioration," a point restated by Cooke et al. (1990) in the context of intraspecific competition. In this form, environmental deterioration arises because a winning lineage has to compete against more winners in successive generations as the population evolves. This "evolutionary environmental deterioration" has different implications for the selection and evolution of traits influenced by resource competition than general environmental change. We reformulate Cooke's model as a quantitative genetic model to show that it is identical in form to more recent developments proposed by quantitative geneticists. This provides a statistical framework for discriminating between the alternative hypotheses of environmental change and environmental deterioration caused by evolutionary change. We also demonstrate that in systems where no phenotypic change has occurred, there are many reasonable biological processes that will generate patterns in predicted breeding values that are consistent with what has been interpreted as cryptic evolution, and care needs to be taken when interpreting these patterns. These processes include mutation, sib competition, and invisible fractions. 相似文献
17.
Randall CN Strasburger D Prozonic J Morris SN Winkie AD Parker GR Cheng D Fennell EM Lanham I Vakil N Huang J Cathcart H Huang R Poduslo SE 《Neurochemical research》2009,34(1):23-28
Multiple genetic variants may contribute to the risk of developing Alzheimer’s disease. We have analyzed polymorphisms in
9 genes to determine whether particular combinations would contribute to this risk. The genes were APOE, LDLr, CST3, CTSD,
TNF, BACE1, MAPT, STH, eNOS, and TFCP2. Three risk groups for the disease were identified. Risk group I was younger, was heterozygous
for the CST3 (GA), CTSD2936 (AG), TNF -308 (AG) genetic variants. Risk group II was older, was homozygous for the −427 APOE
promoter polymorphism (TT), and heterozygous for the MAPT deletion and for the STH variant (QR). Group III had both the youngest
and oldest subjects, were heterozygous for the −863 (AC) and −1031 (CT) TNF promoter polymorphisms. All three groups carried
the APOE 4 allele and were heterozygous for both BACE1 polymorphisms. The control groups were carriers of the APOE 3 allele
and were homozygous for the BACE1 genetic variants.
C. N. Randall, S. N. Morris, A. D. Winkie and G. R. Parker—STAR students.
C. N. Randall, D. Strasburger, J. Prozonic, S. N. Morris, A. D. Winkie, G. R. Parker, D. Cheng and E. M. Fennell contributed
equally to this study.
Special issue article in honor of Dr. George DeVries. 相似文献
18.
Friedreich׳s ataxia is the most important recessive ataxia in the Caucasian population. Loss of frataxin expression affects the production of iron–sulfur clusters and, therefore, mitochondrial energy production. One of the pathological consequences is an increase of iron transport into the mitochondrial compartment leading to a toxic accumulation of reactive iron. However, the mechanism underlying this inappropriate mitochondrial iron accumulation is still unknown. Control and frataxin-deficient flies were fed with an iron diet in order to mimic an iron overload and used to assess various cellular as well as mitochondrial functions. We showed that frataxin-deficient flies were hypersensitive toward dietary iron and developed an iron-dependent decay of mitochondrial functions. In the fly model exhibiting only partial frataxin loss, we demonstrated that the inability to activate ferritin translation and the enhancement of mitochondrial iron uptake via mitoferrin upregulation were likely the key molecular events behind the iron-induced phenotype. Both defects were observed during the normal process of aging, confirming their importance in the progression of the pathology. In an effort to further assess the importance of these mechanisms, we carried out genetic interaction studies. We showed that mitoferrin downregulation improved many of the frataxin-deficient conditions, including nervous system degeneration, whereas mitoferrin overexpression exacerbated most of them. Taken together, this study demonstrates the crucial role of mitoferrin dysfunction in the etiology of Friedreich׳s ataxia and provides evidence that impairment of mitochondrial iron transport could be an effective treatment of the disease. 相似文献
19.
Weeden NF 《Annals of botany》2007,100(5):1017-1025
BACKGROUND AND AIMS: The changes that occur during the domestication of crops such as maize and common bean appear to be controlled by relatively few genes. This study investigates the genetic basis of domestication in pea (Pisum sativum) and compares the genes involved with those determined to be important in common bean domestication. METHODS: Quantitative trait loci and classical genetic analysis are used to investigate and identify the genes modified at three stages of the domestication process. Five recombinant inbred populations involving crosses between different lines representing different stages are examined. KEY RESULTS: A minimum of 15 known genes, in addition to a relatively few major quantitative trait loci, are identified as being critical to the domestication process. These genes control traits such as pod dehiscence, seed dormancy, seed size and other seed quality characters, stem height, root mass, and harvest index. Several of the genes have pleiotropic effects that in species possessing a more rudimentary genetic characterization might have been interpreted as clusters of genes. Very little evidence for gene clustering was found in pea. When compared with common bean, pea has used a different set of genes to produce the same or similar phenotypic changes. CONCLUSIONS: Similar to results for common bean, relatively few genes appear to have been modified during the domestication of pea. However, the genes involved are different, and there does not appear to be a common genetic basis to 'domestication syndrome' in the Fabaceae. 相似文献
20.
The aggregation or oligomerization of amyloid-β (Aβ) peptide is thought to be the primary causative event in the pathogenesis of Alzheimer's disease (AD). Considerable in vitro evidence indicates that the aggregation/oligomerization of Aβ is promoted in the presence of Zn; however, the functional role of Zn in AD pathogenesis is still not well clarified in vivo. Zn is imported into the brain mainly through the solute-linked carrier (Slc) 39 family transporters. Using a genetically tractable Drosophila model, we found that the expression of dZip1, the orthologue of human Slc39 family transporter hZip1 in Drosophila, was altered in the brains of Aβ42-expressing flies, and Zn homeostasis could be modulated by forcible dZip1 expression changes. An array of phenotypes associated with Aβ expression could be modified by altering dZip1 expression. Importantly, Aβ42 fibril deposits as well as its SDS-soluble form were dramatically reduced upon dZip1 inhibition, resulting in less neurodegeneration, significantly improved cognitive performance, and prolonged lifespan of the Aβ42-transgenic flies. These findings suggest that zinc contributes significantly to the Aβ pathology, and manipulation of zinc transporters in AD brains may provide a novel therapeutic strategy. 相似文献