Functional and behavioral consequences of Parkinson's disease-associated LRRK2-G2019S mutation.

Abstract:

:LRRK2 mutation is the most common inherited, autosomal dominant cause of Parkinson's disease (PD) and has also been observed in sporadic cases. Most mutations result in increased LRRK2 kinase activity. LRRK2 is highly expressed in brain regions that receive dense, convergent innervation by dopaminergic and glutamatergic axons, and its levels rise developmentally coincident with glutamatergic synapse formation. The onset and timing of expression suggests strongly that LRRK2 regulates the development, maturation and function of synapses. Several lines of data in mice show that LRRK2-G2019S, the most common LRRK2 mutation, produces an abnormal gain of pathological function that affects synaptic activity, spine morphology, persistent forms of synapse plasticity and behavioral responses to social stress. Effects of the mutation can be detected as early as the second week of postnatal development and can last or have consequences that extend into adulthood and occur in the absence of dopamine loss. These data suggest that the generation of neural circuits that support complex behaviors is modified by LRRK2-G2019S. Whether such alterations impart vulnerability to neurons directly or indirectly, they bring to the forefront the idea that neural circuits within which dopamine neurons eventually degenerate are assembled and utilized in ways that are distinct from circuits that lack this mutation and may contribute to non-motor symptoms observed in humans with PD.

journal_name

Biochem Soc Trans

authors

Benson DL,Matikainen-Ankney BA,Hussein A,Huntley GW

doi

10.1042/BST20180468

subject

Has Abstract

pub_date

2018-12-17 00:00:00

pages

1697-1705

issue

6

eissn

0300-5127

issn

1470-8752

pii

BST20180468

journal_volume

46

pub_type

杂志文章,评审
  • Post-translational modification of nucleoid-associated proteins: an extra layer of functional modulation in bacteria?

    abstract::Post-translational modification (PTM) of histones has been investigated in eukaryotes for years, revealing its widespread occurrence and functional importance. Many PTMs affect chromatin folding and gene activity. Only recently the occurrence of such modifications has been recognized in bacteria. However, it is unclea...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/BST20180488

    authors: Dilweg IW,Dame RT

    更新日期:2018-10-19 00:00:00

  • Atomic force microscopy of virus shells.

    abstract::Microscopes are used to characterize small objects with the help of probes that interact with the specimen, such as photons and electrons in optical and electron microscopies, respectively. In atomic force microscopy (AFM), the probe is a nanometric tip located at the end of a microcantilever which palpates the specim...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/BST20160316

    authors: Moreno-Madrid F,Martín-González N,Llauró A,Ortega-Esteban A,Hernando-Pérez M,Douglas T,Schaap IA,de Pablo PJ

    更新日期:2017-04-15 00:00:00

  • Mitotic motors and chromosome segregation: the mechanism of anaphase B.

    abstract::Anaphase B spindle elongation plays an important role in chromosome segregation. In the present paper, we discuss our model for anaphase B in Drosophila syncytial embryos, in which spindle elongation depends on an ip (interpolar) MT (microtubule) sliding filament mechanism generated by homotetrameric kinesin-5 motors ...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/BST0391149

    authors: Brust-Mascher I,Scholey JM

    更新日期:2011-10-01 00:00:00

  • Lectin-epithelial interactions in the human colon.

    abstract::Similar changes in glycosylation occur in the colonic epithelium in inflammatory conditions such as ulcerative colitis and Crohn's disease and also in colon cancer and precancerous adenomatous polyps. They include reduced length of O-glycans, reduced sulfation, increased sialylation and increased expression of oncofet...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/BST0361482

    authors: Rhodes JM,Campbell BJ,Yu LG

    更新日期:2008-12-01 00:00:00

  • The evolutionary dynamics of venom toxins made by insects and other animals.

    abstract::Animal venoms are recognised as unique biological systems in which to study molecular evolution. Venom use has evolved numerous times among the insects, and insects today use venom to capture prey, defend themselves from predators, or to subdue and modulate host responses during parasitism. However, little is known ab...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章

    doi:10.1042/BST20190820

    authors: Walker AA

    更新日期:2020-08-28 00:00:00

  • Protein kinase C in cellular transformation: a valid target for therapy?

    abstract::The protein kinase C (PKC) family of serine/threonine protein kinases share structural homology, while exhibiting substantial functional diversity. PKC isoforms are ubiquitously expressed in tissues which makes it difficult to define roles for individual isoforms, with complexity compounded by the finding that PKC iso...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/BST20140255

    authors: Tarafdar A,Michie AM

    更新日期:2014-12-01 00:00:00

  • The role of TOG domains in microtubule plus end dynamics.

    abstract::The XMAP215 (Xenopus microtubule-associated protein 215) and CLASP [CLIP-170 (cytoskeletal linker protein 170) associated protein] microtubule plus end tracking families play central roles in the regulation of interphase microtubule dynamics and the proper formation of mitotic spindle architecture and flux. XMAP215 me...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/BST0371002

    authors: Slep KC

    更新日期:2009-10-01 00:00:00

  • ESCRT proteins, endosome organization and mitogenic receptor down-regulation.

    abstract::Mitogenic tyrosine kinase receptors such as the EGFR (epidermal growth factor receptor) are endocytosed once they are activated at the cell surface. After reaching the early endosome, they are ubiquitinated within their cytosolic domain and are consequently sorted away from recycling receptors. They are then incorpora...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/BST0370146

    authors: Woodman P

    更新日期:2009-02-01 00:00:00

  • Functions of the proteasome: from protein degradation and immune surveillance to cancer therapy.

    abstract::This review focuses on recent insights into the mechanisms and the biological functions of the proteasome. This large ATP-dependent proteolytic complex is the main site for protein degradation in mammalian cells and catalyses the rapid degradation of ubiquitinated proteins, and is the source of most antigenic peptides...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/BST0350012

    authors: Goldberg AL

    更新日期:2007-02-01 00:00:00

  • Structural elements involved in activation of the gamma-aminobutyric acid type A (GABAA) receptor.

    abstract::Ligand-gated ion channels function as rapid signal transducers, converting chemical signals (in the form of neurotransmitters) into electrical signals in the postsynaptic neuron. This is achieved by the recognition of neurotransmitter at its specific-binding sites, which then triggers the opening of an ion channel ('g...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/BST0320540

    authors: Kash TL,Trudell JR,Harrison NL

    更新日期:2004-06-01 00:00:00

  • Studying biomolecular complexes with pulsed electron-electron double resonance spectroscopy.

    abstract::The function of biomolecules is intrinsically linked to their structure and the complexes they form during function. Techniques for the determination of structures and dynamics of these nanometre assemblies are therefore important for an understanding on the molecular level. PELDOR (pulsed electron-electron double res...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/BST0390128

    authors: Reginsson GW,Schiemann O

    更新日期:2011-01-01 00:00:00

  • Mechanisms of MAPK signalling specificity.

    abstract::MAPK (mitogen-activated protein kinase) signalling pathways contribute to the regulation of diverse responses, including normal and pathological aspects of cell growth, division, differentiation and death. Their ubiquity and versatility raise the issue of how they achieve specific coupling of signal with cellular resp...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章

    doi:10.1042/BST0340837

    authors: Bardwell L

    更新日期:2006-11-01 00:00:00

  • A new approach for the investigation of reperfusion-related brain injury.

    abstract::Effective stroke therapies require recanalization of occluded cerebral blood vessels; however, early reperfusion can cause BBB (blood-brain barrier) injury, leading to cerebral oedema and/or devastating brain haemorrhage. These complications of early reperfusion, which result from excess production of ROS (reactive ox...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章

    doi:10.1042/BST0341366

    authors: Maier CM,Hsieh L,Crandall T,Narasimhan P,Chan PH

    更新日期:2006-12-01 00:00:00

  • AMP-activated protein kinase regulates gene expression by direct phosphorylation of nuclear proteins.

    abstract::One of the primary functions of AMP-activated protein kinase (AMPK) is to regulate the metabolic pathways in response to reduced cellular energy charge. Most of the known targets of the kinase are cytoplasmic enzymes involved in both catabolic and anabolic metabolism. In addition, activation of AMPK in many cells resu...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/bst0310224

    authors: Leff T

    更新日期:2003-02-01 00:00:00

  • Investigating mitochondrial radical production using targeted probes.

    abstract::A range of mitochondria-targeted probe molecules that comprise a lipophilic cation covalently attached to an active moiety have been developed. The lipophilic cation causes the accumulation of these molecules into mitochondria, driven by the mitochondrial membrane potential. To date, we have targeted antioxidants, spi...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章

    doi:10.1042/BST0321011

    authors: Murphy MP

    更新日期:2004-12-01 00:00:00

  • Influenza fusion peptides.

    abstract::The 'fusion peptides' of a group of enveloped viruses that includes influenza, paramyxo-, retro-and filo-viruses are N-terminal regions of their membrane fusion proteins generated by cleavage of non-functional precursors. For the influenza membrane fusion protein, haemagglutinin (HA), the three-dimensional structures ...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/bst0290623

    authors: Skehel JJ,Cross K,Steinhauer D,Wiley DC

    更新日期:2001-08-01 00:00:00

  • Marine glycosaminoglycan-like carbohydrates as potential drug candidates for infectious disease.

    abstract::Glycosaminoglycans (GAGs), present in the extracellular matrix, are exploited by numerous, distinct microbes for cellular attachment, adhesion, invasion and evasion of the host immune system. Glycosaminoglycans, including the widely used, clinical anticoagulant heparin and semi-synthetic analogues thereof, have been r...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/BST20170404

    authors: Mycroft-West CJ,Yates EA,Skidmore MA

    更新日期:2018-08-20 00:00:00

  • Coagulation cascade proteases and tissue fibrosis.

    abstract::Fibrotic disorders of the liver, kidney and lung are associated with excessive deposition of extracellular matrix proteins and ongoing coagulation-cascade activity. In addition to their critical roles in blood coagulation, thrombin and the immediate upstream coagulation proteases, Factors Xa and VIIa, influence numero...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/

    authors: Chambers RC,Laurent GJ

    更新日期:2002-04-01 00:00:00

  • Calcium oscillations in T-cells: mechanisms and consequences for gene expression.

    abstract::[Ca(2+)](i) (intracellular Ca(2+) concentration) oscillations play a central role in the activation of T-lymphocytes by antigen. Oscillations in T-cells are absolutely dependent on Ca(2+) influx through store-operated CRAC channels (Ca(2+)-release-activated Ca(2+) channels), and evidence suggests that they arise from ...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/bst0310925

    authors: Lewis RS

    更新日期:2003-10-01 00:00:00

  • The benefit of DNA supercoiling during replication.

    abstract::DNA topology changes dynamically during DNA replication. Supercoiling, precatenation, catenation and knotting interplay throughout the process that is finely regulated by DNA topoisomerases. In the present article, we provide an overview of theoretical and experimental approaches to understand the interplay between va...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/BST20120281

    authors: Schvartzman JB,Martínez-Robles ML,Hernández P,Krimer DB

    更新日期:2013-04-01 00:00:00

  • The quest to achieve the detailed structural and functional characterization of CymA.

    abstract::Shewanella oneidensis MR-1 is a sediment organism capable of dissimilatory reduction of insoluble metal compounds such as those of Fe(II) and Mn(IV). This bacterium has been used as a model organism for potential applications in bioremediation of contaminated environments and in the production of energy in microbial f...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/BST20120114

    authors: Louro RO,Paquete CM

    更新日期:2012-12-01 00:00:00

  • Properties and inhibition of the first two enzymes of the non-mevalonate pathway of isoprenoid biosynthesis.

    abstract::Enzymes of the 1-deoxy-D-xylulose 5-phosphate/2-C-methylerythritol 4-phosphate (DOXP/MEP) pathway are targets for new herbicides and antibacterial drugs. Until now, no inhibitors for the DOXP synthase have been known of. We show that one of the breakdown products of the herbicide clomazone affects the DOXP synthase. O...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章

    doi:

    authors: Mueller C,Schwender J,Zeidler J,Lichtenthaler HK

    更新日期:2000-12-01 00:00:00

  • Probing coupled motions in enzymatic hydrogen tunnelling reactions.

    abstract::Much work has gone into understanding the physical basis of the enormous catalytic power of enzymes over the last 50 years or so. Nevertheless, the detailed mechanism used by Nature's catalysts to speed chemical transformations remains elusive. DHFR (dihydrofolate reductase) has served as a paradigm to study the relat...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/BST0370349

    authors: Allemann RK,Evans RM,Loveridge EJ

    更新日期:2009-04-01 00:00:00

  • Blood genomic profiling: novel diagnostic and therapeutic strategies for stroke?

    abstract::Findings from gene expression profiling studies are leading to new diagnostic and therapeutic strategies that can be applied in medical practice, especially in the field of oncology. Promising results of gene expression profiling of the peripheral blood in patients with ischaemic stroke have been obtained in recent pi...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/BST0341313

    authors: Baird AE

    更新日期:2006-12-01 00:00:00

  • Frequency modulated translocational oscillations of Nrf2, a transcription factor functioning like a wireless sensor.

    abstract::The discovery that nuclear factor erythroid 2-related factor 2 (Nrf2) undergoes translocational oscillations from cytoplasm to nucleus in human cells with frequency modulation linked to activation of a stress-stimulated cytoprotective response raises the prospect that the Nrf2 works mechanistically analogous to a wire...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章

    doi:10.1042/BST20150060

    authors: Xue M,Momiji H,Rabbani N,Bretschneider T,Rand DA,Thornalley PJ

    更新日期:2015-08-01 00:00:00

  • HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand?

    abstract::A novel strategy to treat anxiety and fear-related disorders such as phobias, panic and PTSD (post-traumatic stress disorder) is combining CBT (cognitive behavioural therapy), including extinction-based exposure therapy, with cognitive enhancers. By targeting and boosting mechanisms underlying learning, drug developme...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/BST20130233

    authors: Whittle N,Singewald N

    更新日期:2014-04-01 00:00:00

  • New strategies for cartilage regeneration exploiting selected glycosaminoglycans to enhance cell fate determination.

    abstract::Most research strategies for cartilage tissue engineering use extended culture with complex media loaded with costly GFs (growth factors) to drive tissue assembly and yet they result in the production of cartilage with inferior mechanical and structural properties compared with the natural tissue. Recent evidence sugg...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章

    doi:10.1042/BST20140031

    authors: Ayerst BI,Day AJ,Nurcombe V,Cool SM,Merry CL

    更新日期:2014-06-01 00:00:00

  • Post-transcriptional control of mitochondrial protein composition in changing environmental conditions.

    abstract::In fluctuating environmental conditions, organisms must modulate their bioenergetic production in order to maintain cellular homeostasis for optimal fitness. Mitochondria are hubs for metabolite and energy generation. Mitochondria are also highly dynamic in their function: modulating their composition, size, density, ...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章

    doi:10.1042/BST20200250

    authors: Tsuboi T,Leff J,Zid BM

    更新日期:2020-11-27 00:00:00

  • Poly(A)-binding proteins are required for diverse biological processes in metazoans.

    abstract::PABPs [poly(A)-binding proteins] bind to the poly(A) tail of eukaryotic mRNAs and are conserved in species ranging from yeast to human. The prototypical cytoplasmic member, PABP1, is a multifunctional RNA-binding protein with roles in global and mRNA-specific translation and stability, consistent with a function as a ...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章,评审

    doi:10.1042/BST20140111

    authors: Smith RW,Blee TK,Gray NK

    更新日期:2014-08-01 00:00:00

  • Chaperone-assisted assembly of the proteasome core particle.

    abstract::The 26S proteasome is a non-lysosomal protease in the cytosol and nucleus of eukaryotic cells. Its main function is to mediate ubiquitin-dependent proteolysis. The 26S proteasome is a multimeric complex composed by the 20S proteasome CP (core particle) and the 19S RPs (regulatory particles). Although the atomic struct...

    journal_title:Biochemical Society transactions

    pub_type: 杂志文章

    doi:10.1042/BST0380029

    authors: Matias AC,Ramos PC,Dohmen RJ

    更新日期:2010-02-01 00:00:00