Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin

Autosomal recessive juvenile parkinsonism (AR-JP) is an early-onset form of Parkinson's disease characterized by motor disturbances and dopaminergic neurodegeneration. To address its underlying molecular pathogenesis, we generated and characterized loss-of-function mutants of Drosophila PTEN-induced putative kinase 1 (PINK1), a novel AR-JP-linked gene. Here, we show that PINK1 mutants exhibit indirect flight muscle and dopaminergic neuronal degeneration accompanied by locomotive defects. Furthermore, transmission electron microscopy analysis and a rescue experiment with Drosophila Bcl-2 demonstrated that mitochondrial dysfunction accounts for the degenerative changes in all phenotypes of PINK1 mutants. Notably, we also found that PINK1 mutants share marked phenotypic similarities with parkin mutants. Transgenic expression of Parkin markedly ameliorated all PINK1 loss-of-function phenotypes, but not vice versa, suggesting that Parkin functions downstream of PINK1. Taken together, our genetic evidence clearly establishes that Parkin and PINK1 act in a common pathway in maintaining mitochondrial integrity and function in both muscles and dopaminergic neurons.     

A Drosophila model of Parkinson's disease

Parkinson's disease is a common neurodegenerative syndrome characterized by loss of dopaminergic neurons in the substantia nigra, formation of filamentous intraneuronal inclusions (Lewy bodies) and an extrapyramidal movement disorder. Mutations in the alpha-synuclein gene are linked to familial Parkinson's disease and alpha-synuclein accumulates in Lewy bodies and Lewy neurites. Here we express normal and mutant forms of alpha-synuclein in Drosophila and produce adult-onset loss of dopaminergic neurons, filamentous intraneuronal inclusions containing alpha-synuclein and locomotor dysfunction. Our Drosophila model thus recapitulates the essential features of the human disorder, and makes possible a powerful genetic approach to Parkinson's disease.     

Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1

Parkinson's disease is a pervasive, ageing-related neurodegenerative disease the cardinal motor symptoms of which reflect the loss of a small group of neurons, the dopaminergic neurons in the substantia nigra pars compacta (SNc). Mitochondrial oxidant stress is widely viewed as being responsible for this loss, but why these particular neurons should be stressed is a mystery. Here we show, using transgenic mice that expressed a redox-sensitive variant of green fluorescent protein targeted to the mitochondrial matrix, that the engagement of plasma membrane L-type calcium channels during normal autonomous pacemaking created an oxidant stress that was specific to vulnerable SNc dopaminergic neurons. The oxidant stress engaged defences that induced transient, mild mitochondrial depolarization or uncoupling. The mild uncoupling was not affected by deletion of cyclophilin D, which is a component of the permeability transition pore, but was attenuated by genipin and purine nucleotides, which are antagonists of cloned uncoupling proteins. Knocking out DJ-1 (also known as PARK7 in humans and Park7 in mice), which is a gene associated with an early-onset form of Parkinson's disease, downregulated the expression of two uncoupling proteins (UCP4 (SLC25A27) and UCP5 (SLC25A14)), compromised calcium-induced uncoupling and increased oxidation of matrix proteins specifically in SNc dopaminergic neurons. Because drugs approved for human use can antagonize calcium entry through L-type channels, these results point to a novel neuroprotective strategy for both idiopathic and familial forms of Parkinson's disease.     

植物细胞质雄性不育分子机理研究

本文综述了植物细胞质雄性不育分子机理的研究进展。主要介绍了植物线粒体DNA、线粒体RNA和线粒体蛋白质与细胞质雄性不育的关系,同时对植物叶绿体及核质互作与细胞质雄性不育的关系进行了综述,并对今后的研究前景进行了展望。     

SH-SY5Y与U87细胞共培养条件性培养基可降低N-甲基-salsolinol介导THP-1细胞的凋亡

 神经免疫在帕金森病(PD)的致病机理中发挥重要的作用,PD 患者的外周血淋巴细胞的数量发生了变化,提示外周免疫系统在PD 的发生发展中发挥一定的作用。但是外周单核细胞(PBMC)在其中发挥的具体作用尚不清楚。外源性神经毒素(MPTP)类似物,内源性神经毒素(NMSal)可能是导致PD 发生的一种因素。研究采用NMSal 损伤的SH-SY5Y与U87 细胞共培养的条件性培养基培养外周单核细胞THP-1,探讨NMSal 损伤的多巴胺能神经元细胞对外周单核细胞的影响。结果表明,该条件性培养基可以降低NMSal 毒性诱导的THP-1 细胞的凋亡、氧化应激水平(MDA 和H₂O₂)、线粒体的损伤和凋亡相关蛋白FADD、Bax 和caspase3 的表达和活化水平。PD 病人中损伤的多巴胺能神经元与星形胶质细胞的相互作用可能会影响PBMC,进而影响PD 病情的进展。     

葱天然雄性不育系花药的形态解剖学研究

通过石蜡切片法和涂片法，对葱（ＡｌｉｕｍｆｉｓｔｕｌｏｓｕｍＬ．）天然雄性不育系成熟花药的形态结构进行了解剖学研究。发现了雄性不育系成熟花药的形态特征是产生的花粉少且花粉空瘪。本文还初步探讨了造成葱性性不育的时期和原因，认为葱天然雄性不育系的不育发生时期应在小孢子时期或是接近双核期。     

帕金森病研究进展

 帕金森病（PD）是常见的神经系统变性疾病,典型的PD病理表现为脑中黑质多巴胺神经元退行性变和路易小体沉积,但这些改变不能完全解释PD产生的临床症状,目前PD的发病原因及机制尚不明确,尚未建立系统的早期诊断及保护治疗方式。随着诊断及治疗技术的提高,生物学标记物、脑网络及神经调控等有望为PD早期诊断、机制探索及个体化治疗提供基础。本文综述了PD在生物学标记物、脑网络研究及神经调控治疗领域的研究进展。     

Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo

In Parkinson's disease, brain dopamine neurons degenerate most prominently in the substantia nigra. Neurotrophic factors promote survival, differentiation and maintenance of neurons in developing and adult vertebrate nervous system. The most potent neurotrophic factor for dopamine neurons described so far is the glial-cell-line-derived neurotrophic factor (GDNF). Here we have identified a conserved dopamine neurotrophic factor (CDNF) as a trophic factor for dopamine neurons. CDNF, together with its previously described vertebrate and invertebrate homologue the mesencephalic-astrocyte-derived neurotrophic factor, is a secreted protein with eight conserved cysteine residues, predicting a unique protein fold and defining a new, evolutionarily conserved protein family. CDNF (Armetl1) is expressed in several tissues of mouse and human, including the mouse embryonic and postnatal brain. In vivo, CDNF prevented the 6-hydroxydopamine (6-OHDA)-induced degeneration of dopaminergic neurons in a rat experimental model of Parkinson's disease. A single injection of CDNF before 6-OHDA delivery into the striatum significantly reduced amphetamine-induced ipsilateral turning behaviour and almost completely rescued dopaminergic tyrosine-hydroxylase-positive cells in the substantia nigra. When administered four weeks after 6-OHDA, intrastriatal injection of CDNF was able to restore the dopaminergic function and prevent the degeneration of dopaminergic neurons in substantia nigra. Thus, CDNF was at least as efficient as GDNF in both experimental settings. Our results suggest that CDNF might be beneficial for the treatment of Parkinson's disease.     

Susceptibility to leprosy is associated with PARK2 and PACRG

Leprosy is caused by Mycobacterium leprae and affects about 700,000 individuals each year. It has long been thought that leprosy has a strong genetic component, and recently we mapped a leprosy susceptibility locus to chromosome 6 region q25-q26 (ref. 3). Here we investigate this region further by using a systematic association scan of the chromosomal interval most likely to harbour this leprosy susceptibility locus. In 197 Vietnamese families we found a significant association between leprosy and 17 markers located in a block of approx. 80 kilobases overlapping the 5' regulatory region shared by the Parkinson's disease gene PARK2 and the co-regulated gene PACRG. Possession of as few as two of the 17 risk alleles was highly predictive of leprosy. This was confirmed in a sample of 975 unrelated leprosy cases and controls from Brazil in whom the same alleles were strongly associated with leprosy. Variants in the regulatory region shared by PARK2 and PACRG therefore act as common risk factors for leprosy.     

Mitochondrial membrane remodelling regulated by a conserved rhomboid protease

Rhomboid proteins are intramembrane serine proteases that activate epidermal growth factor receptor (EGFR) signalling in Drosophila. Rhomboids are conserved throughout evolution, and even in eukaryotes their existence in species with no EGFRs implies that they must have additional roles. Here we report that Saccharomyces cerevisiae has two rhomboids, which we have named Rbd1p and Rbd2p. RBD1 deletion results in a respiratory defect; consistent with this, Rbd1p is localized in the inner mitochondrial membrane and mutant cells have disrupted mitochondria. We have identified two substrates of Rbd1p: cytochrome c peroxidase (Ccp1p); and a dynamin-like GTPase (Mgm1p), which is involved in mitochondrial membrane fusion. Rbd1p mutants are indistinguishable from Mgm1p mutants, indicating that Mgm1p is a key substrate of Rbd1p and explaining the rbd1Delta mitochondrial phenotype. Our data indicate that mitochondrial membrane remodelling is regulated by cleavage of Mgm1p and show that intramembrane proteolysis by rhomboids controls cellular processes other than signalling. In addition, mitochondrial rhomboids are conserved throughout eukaryotes and the mammalian homologue, PARL, rescues the yeast mutant, suggesting that these proteins represent a functionally conserved subclass of rhomboid proteases.     

The genetic and molecular basis of cytoplasmic male sterility and fertility restoration in rice

Cytoplasmic male sterility （CMS） is a maternally inherited characteristic found in many （〉150） plant species. CMS/restoration systems are useful tools for hybrid seed production, and are ideal models for study of the interactions between nuclear and mitochondrial genomes. CMS/restoration systems in rice have been widely used for hybrid seed production, greatly contributing to the food supply. This article reviews the progress of the studies on the genetic and molecular basis of cytoplasmic male sterility and fertility restoration in rice.     

鱼藤酮诱导SH-SY5Y细胞对过氧化氢损伤易感性增高与硫氧还蛋白下调有关

帕金森病(PD)的发病机制与线粒体呼吸链复合物I(complex I)活性降低以及氧化应激损伤密切相关.使用complex I特异性抑制物鱼藤酮,损伤人神经母细胞瘤SH-SY5Y细胞后,给予H2O2造成氧化应激损伤,以研究细胞抗氧化损伤能力变化的可能机制.结果表明,鱼藤酮处理后,细胞对H2O2所致氧化损伤的易感性增高,且细胞形态及细胞存活率的改变与鱼藤酮浓度呈量效关系.与此同时,细胞内抗氧化蛋白之一,硫氧还蛋白(thioredoxin)水平在细胞损伤时明显下降.以上结果表明,线粒体complex I抑制对细胞氧化应激易感性的影响可能与胞内硫氧还蛋白水平降低有关,提示硫氧还蛋白在诊断神经元损伤和神经保护中有一定的运用前景.     

Presenilin is required for proper morphology and function of neurons in C. elegans

Mutations in the human presenilin genes cause the most frequent and aggressive forms of familial Alzheimer's disease (FAD). Here we show that in addition to its role in cell fate decisions in non-neuronal tissues, presenilin activity is required in terminally differentiated neurons in vivo. Mutations in the Caenorhabditis elegans presenilin genes sel-12 and hop-1 result in a defect in the temperature memory of the animals. This defect is caused by the loss of presenilin function in two cholinergic interneurons that display neurite morphology defects in presenilin mutants. The morphology and function of the affected neurons in sel-12 mutant animals can be restored by expressing sel-12 only in these cells. The wild-type human presenilin PS1, but not the FAD mutant PS1 A246E, can also rescue these morphological defects. As lin-12 mutant animals display similar morphological and functional defects to presenilin mutants, we suggest that presenilins mediate their activity in postmitotic neurons by facilitating Notch signalling. These data indicate cell-autonomous and evolutionarily conserved control of neural morphology and function by presenilins.     

Genetic rescue of inviable hybrids between Drosophila melanogaster and its sibling species

Post-mating mechanisms are central to the establishment of reproductive isolation between different, but closely related, species. Post-mating isolation mechanisms include hybrid breakdown, hybrid sterility and hybrid lethality and may, in some cases, be reinforced by pre-mating mechanisms such as ethological differentiation. In the Drosophila melanogaster species sub-group post-mating reproductive isolation is ensured by both the inviability and the sterility of hybrids. For example when D. melanogaster females are crossed to D. simulans males the hybrid progeny are normally all female; the hybrid males die as third instar larvae. The viable hybrid females are totally sterile. Little is known of the genetic basis for either hybrid sterility or hybrid inviability, although Coyne and others have begun a genetic analysis of the sterility of hybrids within this species sub-group. We have discovered a single gene difference that rescues the otherwise inviable male hybrids from the cross between D. melanogaster females and males of its three closest relatives. The study of this locus may shed light on the genetic control of both speciation and development.     

Drosophila TCTP is essential for growth and proliferation through regulation of dRheb GTPase

Cellular growth and proliferation are coordinated during organogenesis. Misregulation of these processes leads to pathological conditions such as cancer. Tuberous sclerosis (TSC) is a benign tumour syndrome caused by mutations in either TSC1 or TSC2 tumour suppressor genes. Studies in Drosophila and other organisms have identified TSC signalling as a conserved pathway for growth control. Activation of the TSC pathway is mediated by Rheb (Ras homologue enriched in brain), a Ras superfamily GTPase. Rheb is a direct target of TSC2 and is negatively regulated by its GTPase-activating protein activity. However, molecules required for positive regulation of Rheb have not been identified. Here we show that a conserved protein, translationally controlled tumour protein (TCTP), is an essential new component of the TSC-Rheb pathway. Reducing Drosophila TCTP (dTCTP) levels reduces cell size, cell number and organ size, which mimics Drosophila Rheb (dRheb) mutant phenotypes. dTCTP is genetically epistatic to Tsc1 and dRheb, but acts upstream of dS6k, a downstream target of dRheb. dTCTP directly associates with dRheb and displays guanine nucleotide exchange activity with it in vivo and in vitro. Human TCTP (hTCTP) shows similar biochemical properties compared to dTCTP and can rescue dTCTP mutant phenotypes, suggesting that the function of TCTP in the TSC pathway is evolutionarily conserved. Our studies identify TCTP as a direct regulator of Rheb and a potential therapeutic target for TSC disease.