当前位置： SCI文献检索 > HUMAN MOLECULAR GENETICS期刊下所有文献 > Loss of thymidine kinase 2 alters neuronal bioenergetics and leads to neurodegeneration.

Loss of thymidine kinase 2 alters neuronal bioenergetics and leads to neurodegeneration.

Abstract：

:Mutations of thymidine kinase 2 (TK2), an essential component of the mitochondrial nucleotide salvage pathway, can give rise to mitochondrial DNA (mtDNA) depletion syndromes (MDS). These clinically heterogeneous disorders are characterized by severe reduction in mtDNA copy number in affected tissues and are associated with progressive myopathy, hepatopathy and/or encephalopathy, depending in part on the underlying nuclear genetic defect. Mutations of TK2 have previously been associated with an isolated myopathic form of MDS (OMIM 609560). However, more recently, neurological phenotypes have been demonstrated in patients carrying TK2 mutations, thus suggesting that loss of TK2 results in neuronal dysfunction. Here, we directly address the role of TK2 in neuronal homeostasis using a knockout mouse model. We demonstrate that in vivo loss of TK2 activity leads to a severe ataxic phenotype, accompanied by reduced mtDNA copy number and decreased steady-state levels of electron transport chain proteins in the brain. In TK2-deficient cerebellar neurons, these abnormalities are associated with impaired mitochondrial bioenergetic function, aberrant mitochondrial ultrastructure and degeneration of selected neuronal types. Overall, our findings demonstrate that TK2 deficiency leads to neuronal dysfunction in vivo, and have important implications for understanding the mechanisms of neurological impairment in MDS.

journal_name

Hum Mol Genet

journal_title

Human molecular genetics

authors

Bartesaghi S,Betts-Henderson J,Cain K,Dinsdale D,Zhou X,Karlsson A,Salomoni P,Nicotera P

doi

10.1093/hmg/ddq043

subject

Has Abstract

pub_date

2010-05-01 00:00:00

pages

1669-77

issue

9

eissn

0964-6906

issn

1460-2083

pii

ddq043

journal_volume

19

pub_type

杂志文章

相关文献

HUMAN MOLECULAR GENETICS文献大全
  • Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis.

    abstract：:Pheochromocytomas (PCCs) and paragangliomas (PGLs) are chromaffin-cell tumors that arise from the adrenal medulla and extra-adrenal paraganglia, respectively. The dysfunction of genes involved in the cellular response to hypoxia, such as VHL, EGL nine homolog 1, and the succinate dehydrogenase (SDH) genes, leads to a ...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/ddt069

    authors： Comino-Méndez I,de Cubas AA,Bernal C,Álvarez-Escolá C,Sánchez-Malo C,Ramírez-Tortosa CL,Pedrinaci S,Rapizzi E,Ercolino T,Bernini G,Bacca A,Letón R,Pita G,Alonso MR,Leandro-García LJ,Gómez-Graña A,Inglada-Pérez L,Manciko

    更新日期：2013-06-01 00:00:00

  • Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63.

    abstract：:Hay-Wells syndrome, also known as ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome (OMIM 106260), is a rare autosomal dominant disorder characterized by congenital ectodermal dysplasia, including alopecia, scalp infections, dystrophic nails, hypodontia, ankyloblepharon and cleft lip and/or cleft palate. Th...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/10.3.221

    authors： McGrath JA,Duijf PH,Doetsch V,Irvine AD,de Waal R,Vanmolkot KR,Wessagowit V,Kelly A,Atherton DJ,Griffiths WA,Orlow SJ,van Haeringen A,Ausems MG,Yang A,McKeon F,Bamshad MA,Brunner HG,Hamel BC,van Bokhoven H

    更新日期：2001-02-01 00:00:00

  • Functional characterization of the AFF (AF4/FMR2) family of RNA-binding proteins: insights into the molecular pathology of FRAXE intellectual disability.

    abstract：:The AFF (AF4/FMR2) family of genes includes four members: AFF1/AF4, AFF2/FMR2, AFF3/LAF4 and AFF4/AF5q31. AFF2/FMR2 is silenced in FRAXE intellectual disability, while the other three members have been reported to form fusion genes as a consequence of chromosome translocations with the myeloid/lymphoid or mixed lineag...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/ddr069

    authors： Melko M,Douguet D,Bensaid M,Zongaro S,Verheggen C,Gecz J,Bardoni B

    更新日期：2011-05-15 00:00:00

  • Convergent linkage evidence from two Latin-American population isolates supports the presence of a susceptibility locus for bipolar disorder in 5q31-34.

    abstract：:We performed a whole genome microsatellite marker scan in six multiplex families with bipolar (BP) mood disorder ascertained in Antioquia, a historically isolated population from North West Colombia. These families were characterized clinically using the approach employed in independent ongoing studies of BP in the cl...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/ddl254

    authors： Herzberg I,Jasinska A,García J,Jawaheer D,Service S,Kremeyer B,Duque C,Parra MV,Vega J,Ortiz D,Carvajal L,Polanco G,Restrepo GJ,López C,Palacio C,Levinson M,Aldana I,Mathews C,Davanzo P,Molina J,Fournier E,Bejar

    更新日期：2006-11-01 00:00:00

  • Pathways to understanding the genomic aetiology of osteoarthritis.

    abstract：:Osteoarthritis is a common, complex disease with no curative therapy. In this review, we summarize current knowledge on disease aetiopathogenesis and outline genetics and genomics approaches that are helping catalyse a much-needed improved understanding of the biological underpinning of disease development and progres...

    journal_title：Human molecular genetics

    pub_type： 杂志文章,评审

    doi：10.1093/hmg/ddx302

    authors： Cibrián Uhalte E,Wilkinson JM,Southam L,Zeggini E

    更新日期：2017-10-01 00:00:00

  • A region of human chromosome 9p required for testis development contains two genes related to known sexual regulators.

    abstract：:Deletion of the distal short arm of chromosome 9 (9p) has been reported in a number of cases to be associated with gonadal dysgenesis and XY sex reversal, suggesting that this region contains one or more genes required in two copies for normal testis development. Recent studies have greatly narrowed the interval conta...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/8.6.989

    authors： Raymond CS,Parker ED,Kettlewell JR,Brown LG,Page DC,Kusz K,Jaruzelska J,Reinberg Y,Flejter WL,Bardwell VJ,Hirsch B,Zarkower D

    更新日期：1999-06-01 00:00:00

  • A polygenic burden of rare variants across extracellular matrix genes among individuals with adolescent idiopathic scoliosis.

    abstract：:Adolescent idiopathic scoliosis (AIS) is a complex inherited spinal deformity whose etiology has been elusive. While common genetic variants are associated with AIS, they explain only a small portion of disease risk. To explore the role of rare variants in AIS susceptibility, exome sequence data of 391 severe AIS case...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/ddv463

    authors： Haller G,Alvarado D,Mccall K,Yang P,Cruchaga C,Harms M,Goate A,Willing M,Morcuende JA,Baschal E,Miller NH,Wise C,Dobbs MB,Gurnett CA

    更新日期：2016-01-01 00:00:00

  • Long-lived epigenetic interactions between perinatal PBDE exposure and Mecp2308 mutation.

    abstract：:The widespread use of persistent organic polybrominated diphenyl ethers (PBDEs) as commercial flame retardants has raised concern about potential long-lived effects on human health. Epigenetic mechanisms, such as DNA methylation, are responsive to environmental influences and have long-lasting consequences. Autism spe...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/dds046

    authors： Woods R,Vallero RO,Golub MS,Suarez JK,Ta TA,Yasui DH,Chi LH,Kostyniak PJ,Pessah IN,Berman RF,LaSalle JM

    更新日期：2012-06-01 00:00:00

  • Homozygous alpha6 integrin mutation in junctional epidermolysis bullosa with congenital duodenal atresia.

    abstract：:Junctional epidermolysis bullosa with congenital pyloric or duodenal atresia is a distinct variant within this group of autosomal recessive blistering skin diseases. In this study we demonstrate, for the first time, a homozygous mutation in the alpha6 integrin gene (ITGA6) in a family with three affected individuals. ...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/6.5.669

    authors： Pulkkinen L,Kimonis VE,Xu Y,Spanou EN,McLean WH,Uitto J

    更新日期：1997-05-01 00:00:00

  • Altered localization, abnormal modification and loss of function of Sigma receptor-1 in amyotrophic lateral sclerosis.

    abstract：:Intracellular accumulations of mutant, misfolded proteins are major pathological hallmarks of amyotrophic lateral sclerosis (ALS) and related disorders. Recently, mutations in Sigma receptor 1 (SigR1) have been found to cause a form of ALS and frontotemporal lobar degeneration (FTLD). Our goal was to pinpoint alterati...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/ddt008

    authors： Prause J,Goswami A,Katona I,Roos A,Schnizler M,Bushuven E,Dreier A,Buchkremer S,Johann S,Beyer C,Deschauer M,Troost D,Weis J

    更新日期：2013-04-15 00:00:00

  • Genetic heterogeneity among uterine leiomyomata: insights into malignant progression.

    abstract：:Uterine leiomyomata (UL), also known as fibroids, are the most common pelvic tumors in women of reproductive age and are the primary indication for hysterectomy in the USA. Many lines of evidence indicate a strong genetic component to the development of these tumors. In fact, approximately 40% of UL have non-random, t...

    journal_title：Human molecular genetics

    pub_type： 杂志文章,评审

    doi：10.1093/hmg/ddm043

    authors： Hodge JC,Morton CC

    更新日期：2007-04-15 00:00:00

  • Localization of motor-related proteins and associated complexes to active, but not inactive, centromeres.

    abstract：:Multicentric chromosomes are often found in tumor cells and certain cell lines. How they are generated is not fully understood, though their stability suggests that they are non-functional during chromosome segregation. Growing evidence has implicated microtubule motor proteins in attachment of chromosomes to the mito...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/7.4.671

    authors： Faulkner NE,Vig B,Echeverri CJ,Wordeman L,Vallee RB

    更新日期：1998-04-01 00:00:00

  • Cell cycle arrest enhances the in vitro cellular toxicity of the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch.

    abstract：:Machado-Joseph disease (MJD) is an inherited neurodegenerative disorder caused by the expansion of the polyglutamine stretch in the MJD gene-encoded protein, ataxin-3. Using a series of deletion constructs expressing ataxin-3 fragments with expanded polyglutamine stretches, we observed aggregate formation and cell dea...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/9.1.69

    authors： Yoshizawa T,Yamagishi Y,Koseki N,Goto J,Yoshida H,Shibasaki F,Shoji S,Kanazawa I

    更新日期：2000-01-01 00:00:00

  • The Leri-Weill and Turner syndrome homeobox gene SHOX encodes a cell-type specific transcriptional activator.

    abstract：:Functional impairment of the human homeobox gene SHOX causes short stature and Madelung deformity in Leri-Weill syndrome (LWS) and has recently been implicated in additional skeletal malformations frequently observed in Turner syndrome. To enhance our understanding of the underlying mechanism of action, we have establ...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/10.26.3083

    authors： Rao E,Blaschke RJ,Marchini A,Niesler B,Burnett M,Rappold GA

    更新日期：2001-12-15 00:00:00

  • COG8 deficiency causes new congenital disorder of glycosylation type IIh.

    abstract：:We describe a new Type II congenital disorder of glycosylation (CDG-II) caused by mutations in the conserved oligomeric Golgi (COG) complex gene, COG8. The patient has severe psychomotor retardation, seizures, failure to thrive and intolerance to wheat and dairy products. Analysis of serum transferrin and total serum ...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/ddm028

    authors： Kranz C,Ng BG,Sun L,Sharma V,Eklund EA,Miura Y,Ungar D,Lupashin V,Winkel RD,Cipollo JF,Costello CE,Loh E,Hong W,Freeze HH

    更新日期：2007-04-01 00:00:00

  • Sacred disease secrets revealed: the genetics of human epilepsy.

    abstract：:Neurons throughout the brain suddenly discharging synchronously and recurrently cause primarily generalized seizures. Discharges localized awhile in one part of the brain cause focal-onset seizures. A genetically determined generalized hyperexcitability had been predicted in primarily generalized seizures, but surpris...

    journal_title：Human molecular genetics

    pub_type： 更正并重新发布的文章,杂志文章,评审

    doi：

    authors： Turnbull J,Lohi H,Kearney JA,Rouleau GA,Delgado-Escueta AV,Meisler MH,Cossette P,Minassian BA

    更新日期：2005-10-15 00:00:00

  • Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2.

    abstract：:Senataxin, encoded by the SETX gene, contributes to multiple aspects of gene expression, including transcription and RNA processing. Mutations in SETX cause the recessive disorder ataxia with oculomotor apraxia type 2 (AOA2) and a dominant juvenile form of amyotrophic lateral sclerosis (ALS4). To assess the functional...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/ddu190

    authors： Fogel BL,Cho E,Wahnich A,Gao F,Becherel OJ,Wang X,Fike F,Chen L,Criscuolo C,De Michele G,Filla A,Collins A,Hahn AF,Gatti RA,Konopka G,Perlman S,Lavin MF,Geschwind DH,Coppola G

    更新日期：2014-09-15 00:00:00

  • A YAC clone map spanning 7.5 megabases of human chromosome band Xq28.

    abstract：:Xq28 has been of special interest in human genetics because a large number of diseases map to this region. As a step in the molecular analysis of the as yet uncloned disease genes, and as a test for the detailed analysis of larger regions of the genome, we have constructed YAC clone contigs covering the 7.5 Mb region ...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/3.12.2137

    authors： Rogner UC,Kioschis P,Wilke K,Gong W,Pick E,Dietrich A,Zechner U,Hameister H,Pragliola A,Herman GE

    更新日期：1994-12-01 00:00:00

  • Dopamine determines the vulnerability of striatal neurons to the N-terminal fragment of mutant huntingtin through the regulation of mitochondrial complex II.

    abstract：:In neurodegenerative disorders associated with primary or secondary mitochondrial defects such as Huntington's disease (HD), cells of the striatum are particularly vulnerable to cell death, although the mechanisms by which this cell death is induced are unclear. Dopamine, found in high concentrations in the striatum, ...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/ddn033

    authors： Benchoua A,Trioulier Y,Diguet E,Malgorn C,Gaillard MC,Dufour N,Elalouf JM,Krajewski S,Hantraye P,Déglon N,Brouillet E

    更新日期：2008-05-15 00:00:00

  • FGFR3 is a target of the homeobox transcription factor SHOX in limb development.

    abstract：:The short stature homeobox gene SHOX encodes a transcription factor which is important for normal limb development. In humans, SHOX deficiency has been associated with various short stature syndromes including Leri-Weill dyschondrosteosis (LWD), Langer mesomelic dysplasia and Turner syndrome as well as non-syndromic i...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/ddr030

    authors： Decker E,Durand C,Bender S,Rödelsperger C,Glaser A,Hecht J,Schneider KU,Rappold G

    更新日期：2011-04-15 00:00:00

  • The inward rectifier potassium channel Kir2.1 is required for osteoblastogenesis.

    abstract：:Andersen's syndrome (AS) is a rare and dominantly inherited pathology, linked to the inwardly rectifying potassium channel Kir2.1. AS patients exhibit a triad of symptoms that include periodic paralysis, cardiac dysrhythmia and bone malformations. Some progress has been made in understanding the contribution of the Ki...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/ddu462

    authors： Sacco S,Giuliano S,Sacconi S,Desnuelle C,Barhanin J,Amri EZ,Bendahhou S

    更新日期：2015-01-15 00:00:00

  • Copper-dependent trafficking of Wilson disease mutant ATP7B proteins.

    abstract：:We have previously developed a functional assay in yeast for the copper transporter, ATP7B, defective in Wilson disease (WND). Analysis of WND variant ATP7B proteins revealed that several were able to completely, or nearly completely, complement a mutant yeast strain in which the ATP7B ortholog CCC2 was disrupted, ind...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/9.13.1927

    authors： Forbes JR,Cox DW

    更新日期：2000-08-12 00:00:00

  • Panning for gold: genome-wide scanning for linkage in type 1 diabetes.

    abstract：:Genome-wide scans for linkage of chromosome regions to type 1 diabetes in affected sib pair families have revealed that the major susceptibility locus resides within the major histocompatibility complex (MHC) on chromosome 6p21 (lambda S = 2.4). It is recognized that the MHC contains multiple susceptibility loci (refe...

    journal_title：Human molecular genetics

    pub_type： 杂志文章,评审

    doi：10.1093/hmg/5.supplement_1.1443

    authors： Todd JA,Farrall M

    更新日期：1996-01-01 00:00:00

  • Utrophin A is essential in mediating the functional adaptations of mdx mouse muscle following chronic AMPK activation.

    abstract：:Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin along muscle fibers. An attractive therapeutic avenue for DMD consists in the upregulation of utrophin A, a protein with high sequence identity and functional redundancy with dystrophin. Recent work has shown that pharmacological interventions th...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/ddu535

    authors： Al-Rewashdy H,Ljubicic V,Lin W,Renaud JM,Jasmin BJ

    更新日期：2015-03-01 00:00:00

  • Modifier genes and non-genetic factors reshape anatomical deficits in Zfp423-deficient mice.

    abstract：:Development of neural circuitry depends on the integration of signaling pathways to coordinate specification, proliferation and differentiation of cell types in the right number, in the right place, at the right time. Zinc finger protein 423 (Zfp423), a 30-zinc finger transcription factor, forms alternate complexes wi...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/ddr300

    authors： Alcaraz WA,Chen E,Valdes P,Kim E,Lo YH,Vo J,Hamilton BA

    更新日期：2011-10-01 00:00:00

  • Defective endocytic trafficking of NPC1 and NPC2 underlying infantile Niemann-Pick type C disease.

    abstract：:Niemann-Pick type C (NPC) disease is a fatal recessively inherited lysosomal cholesterol-sphingolipidosis. Mutations in the NPC1 gene cause approximately 95% of the cases, the rest being caused by NPC2 mutations. Here the molecular basis of a severe infantile form of the disease was dissected. The level of NPC1 protei...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/ddg025

    authors： Blom TS,Linder MD,Snow K,Pihko H,Hess MW,Jokitalo E,Veckman V,Syvänen AC,Ikonen E

    更新日期：2003-02-01 00:00:00

  • Collapsed methylation quantitative trait loci analysis for low frequency and rare variants.

    abstract：BACKGROUND:Single variant approaches have been successful in identifying DNA methylation quantitative trait loci (mQTL), although as with complex traits they lack the statistical power to identify the effects from rare genetic variants. We have undertaken extensive analyses to identify regions of low frequency and rare...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/ddw283

    authors： Richardson TG,Shihab HA,Hemani G,Zheng J,Hannon E,Mill J,Carnero-Montoro E,Bell JT,Lyttleton O,McArdle WL,Ring SM,Rodriguez S,Campbell C,Smith GD,Relton CL,Timpson NJ,Gaunt TR

    更新日期：2016-10-01 00:00:00

  • Enriched rearing improves behavioral responses of an animal model for CNV-based autistic-like traits.

    abstract：:Potocki-Lupski syndrome (PTLS; MIM #610883), characterized by neurobehavioral abnormalities, intellectual disability and congenital anomalies, is caused by a 3.7-Mb duplication in 17p11.2. Neurobehavioral studies determined that ∼70-90% of PTLS subjects tested positive for autism or autism spectrum disorder (ASD). We ...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/dds124

    authors： Lacaria M,Spencer C,Gu W,Paylor R,Lupski JR

    更新日期：2012-07-15 00:00:00

  • Unequal interchromosomal rearrangements may result in elastin gene deletions causing the Williams-Beuren syndrome.

    abstract：:Williams-Beuren syndrome (WBS) is generally the consequence of an interstitial microdeletion at 7q11.23, which includes the elastin gene, thus causing hemizygosity at the elastin gene locus. The origin of the deletion has been reported by many authors to be maternal in approximately 60% and paternal in 40% of cases. S...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/5.12.1893

    authors： Dutly F,Schinzel A

    更新日期：1996-12-01 00:00:00

  • Multiple evidence strands suggest that there may be as few as 19,000 human protein-coding genes.

    abstract：:Determining the full complement of protein-coding genes is a key goal of genome annotation. The most powerful approach for confirming protein-coding potential is the detection of cellular protein expression through peptide mass spectrometry (MS) experiments. Here, we mapped peptides detected in seven large-scale prote...

    journal_title：Human molecular genetics

    pub_type： 杂志文章

    doi：10.1093/hmg/ddu309

    authors： Ezkurdia I,Juan D,Rodriguez JM,Frankish A,Diekhans M,Harrow J,Vazquez J,Valencia A,Tress ML

    更新日期：2014-11-15 00:00:00