Increased levels of phosphoinositides cause neurodegeneration in a Drosophila model of amyotrophic lateral sclerosis.


:The Vesicle-associated membrane protein (VAMP)-Associated Protein B (VAPB) is the causative gene of amyotrophic lateral sclerosis 8 (ALS8) in humans. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective death of motor neurons leading to spasticity, muscle atrophy and paralysis. VAP proteins have been implicated in various cellular processes, including intercellular signalling, synaptic remodelling, lipid transport and membrane trafficking and yet, the molecular mechanisms underlying ALS8 pathogenesis remain poorly understood. We identified the conserved phosphoinositide phosphatase Sac1 as a Drosophila VAP (DVAP)-binding partner and showed that DVAP is required to maintain normal levels of phosphoinositides. Downregulating either Sac1 or DVAP disrupts axonal transport, synaptic growth, synaptic microtubule integrity and the localization of several postsynaptic components. Expression of the disease-causing allele (DVAP-P58S) in a fly model for ALS8 induces neurodegeneration, elicits synaptic defects similar to those of DVAP or Sac1 downregulation and increases phosphoinositide levels. Consistent with a role for Sac1-mediated increase of phosphoinositide levels in ALS8 pathogenesis, we found that Sac1 downregulation induces neurodegeneration in a dosage-dependent manner. In addition, we report that Sac1 is sequestered into the DVAP-P58S-induced aggregates and that reducing phosphoinositide levels rescues the neurodegeneration and suppresses the synaptic phenotypes associated with DVAP-P58S transgenic expression. These data underscore the importance of DVAP-Sac1 interaction in controlling phosphoinositide metabolism and provide mechanistic evidence for a crucial role of phosphoinositide levels in VAP-induced ALS.


Hum Mol Genet


Human molecular genetics


Forrest S,Chai A,Sanhueza M,Marescotti M,Parry K,Georgiev A,Sahota V,Mendez-Castro R,Pennetta G




Has Abstract


2013-07-01 00:00:00














  • Isolation, characterization and mutation analysis of PEX13-defective Chinese hamster ovary cell mutants.

    abstract::We isolated peroxisome biogenesis mutants ZP128 and ZP150 from rat PEX2 -transformed Chinese hamster ovary (CHO) cells, by the 9-(1'-pyrene)nonanol/ultraviolet method. The mutants lacked morphologically recognizable peroxisomes and showed a typical peroxisome assembly-defective phenotype such as a high sensitivity to ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Toyama R,Mukai S,Itagaki A,Tamura S,Shimozawa N,Suzuki Y,Kondo N,Wanders RJ,Fujiki Y

    更新日期:1999-09-01 00:00:00

  • The telomere lengthening mechanism in telomerase-negative immortal human cells does not involve the telomerase RNA subunit.

    abstract::According to the telomere hypothesis of senescence, the progressive shortening of telomeres that occurs upon division of normal somatic cells eventually leads to cellular senescence. The immortalisation of human cells is associated with the acquisition of a telomere maintenance mechanism which is usually dependent upo...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Bryan TM,Marusic L,Bacchetti S,Namba M,Reddel RR

    更新日期:1997-06-01 00:00:00

  • Discrete subcellular partitioning of human retrotransposon RNAs despite a common mechanism of genome insertion.

    abstract::Despite the immense significance retrotransposons have had for genome evolution much about their biology is unknown, including the processes of forming their ribonucleoprotein (RNP) particles and transporting them about the cell. Suppression of retrotransposon expression, together with the presence of retrotransposon ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Goodier JL,Mandal PK,Zhang L,Kazazian HH Jr

    更新日期:2010-05-01 00:00:00

  • IRF4, MC1R and TYR genes are risk factors for actinic keratosis independent of skin color.

    abstract::Actinic keratosis (AK) is a pre-malignant skin disease, highly prevalent in elderly Europeans. This study investigates genetic susceptibility to AK with a genome-wide association study (GWAS). A full body skin examination was performed in 3194 elderly individuals from the Rotterdam Study (RS) of exclusive north-wester...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Jacobs LC,Liu F,Pardo LM,Hofman A,Uitterlinden AG,Kayser M,Nijsten T

    更新日期:2015-06-01 00:00:00

  • Functional characterization of SIM1-associated enhancers.

    abstract::Haploinsufficiency of the single-minded homology 1 (SIM1) gene in humans and mice leads to severe obesity, suggesting that altered expression of SIM1, by way of regulatory elements such as enhancers, could predispose individuals to obesity. Here, we identified transcriptional enhancers that could regulate SIM1, using ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Kim MJ,Oksenberg N,Hoffmann TJ,Vaisse C,Ahituv N

    更新日期:2014-04-01 00:00:00

  • The PINK1/Parkin pathway regulates mitochondrial dynamics and function in mammalian hippocampal and dopaminergic neurons.

    abstract::PTEN-induced putative kinase 1 (PINK1) and Parkin act in a common pathway to regulate mitochondrial dynamics, the involvement of which in the pathogenesis of Parkinson's disease (PD) is increasingly being appreciated. However, how the PINK1/Parkin pathway influences mitochondrial function is not well understood, and t...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Yu W,Sun Y,Guo S,Lu B

    更新日期:2011-08-15 00:00:00

  • Disruption of nesprin-1 produces an Emery Dreifuss muscular dystrophy-like phenotype in mice.

    abstract::Mutations in the gene encoding the inner nuclear membrane proteins lamins A and C produce cardiac and skeletal muscle dysfunction referred to as Emery Dreifuss muscular dystrophy. Lamins A and C participate in the LINC complex that, along with the nesprin and SUN proteins, LInk the Nucleoskeleton with the Cytoskeleton...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Puckelwartz MJ,Kessler E,Zhang Y,Hodzic D,Randles KN,Morris G,Earley JU,Hadhazy M,Holaska JM,Mewborn SK,Pytel P,McNally EM

    更新日期:2009-02-15 00:00:00

  • Haplotypes of the WNK1 gene associate with blood pressure variation in a severely hypertensive population from the British Genetics of Hypertension study.

    abstract::Mutations in the WNK1 gene cause Gordon's syndrome, a rare Mendelian form of hypertension. We assessed whether common WNK1 variants might also contribute to essential hypertension (EH), a multifactorial disorder affecting > 25% of the adult population worldwide. A panel of 19 single nucleotide polymorphisms (SNPs) spa...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Newhouse SJ,Wallace C,Dobson R,Mein C,Pembroke J,Farrall M,Clayton D,Brown M,Samani N,Dominiczak A,Connell JM,Webster J,Lathrop GM,Caulfield M,Munroe PB

    更新日期:2005-07-01 00:00:00

  • A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins.

    abstract::In human type 1 diabetes (T1D) and in its murine model, the major histocompatibility complex (MHC) class II molecules, human leukocyte antigens (HLA)-DQ and -DR and their murine orthologues, IA and IE, are the major genetic determinants. In this report, we have ranked HLA class II molecule-associated T1D risk in a two...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Cucca F,Lampis R,Congia M,Angius E,Nutland S,Bain SC,Barnett AH,Todd JA

    更新日期:2001-09-15 00:00:00

  • A mouse model of Angelman syndrome imprinting defects.

    abstract::Angelman syndrome, Prader-Will syndrome and Dup15q syndrome map to a cluster of imprinted genes located at 15q11-q13. Imprinting at this domain is regulated by an imprinting control region consisting of two distinct elements, the Angelman syndrome imprinting center (AS-IC) and the Prader-Willi syndrome imprinting cent...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Lewis MW,Vargas-Franco D,Morse DA,Resnick JL

    更新日期:2019-01-15 00:00:00

  • Cereblon suppresses the formation of pathogenic protein aggregates in a p62-dependent manner.

    abstract::Formation of protein aggregates is the hallmark of neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and frontotemporal dementia. Many ubiquitin-associated proteins are recruited to protein aggregates, such as sequestosome 1/p62 (p62), parkin, and cereblon (CRBN). However, the roles of thes...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Zhou L,Hao Z,Wang G,Xu G

    更新日期:2018-02-15 00:00:00

  • Analysis of a malsegregating mouse Y chromosome: evidence that the earliest cleavage divisions of the mammalian embryo are non-disjunction-prone.

    abstract::Despite the clinical importance of human aneuploidy, we know little of the causes of mammalian non-disjunction. In part, this reflects the fact that, unlike lower organisms, segregation 'impaired' chromosomes are virtually non-existent in mammals. To address this issue, we have studied the mouse Y chromosome on the BA...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Bean CJ,Hunt PA,Millie EA,Hassold TJ

    更新日期:2001-04-15 00:00:00

  • Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes.

    abstract::Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Twigg SR,Babbs C,van den Elzen ME,Goriely A,Taylor S,McGowan SJ,Giannoulatou E,Lonie L,Ragoussis J,Sadighi Akha E,Knight SJ,Zechi-Ceide RM,Hoogeboom JA,Pober BR,Toriello HV,Wall SA,Rita Passos-Bueno M,Brunner HG,Mathi

    更新日期:2013-04-15 00:00:00

  • Huntingtin affinity for partners is not changed by polyglutamine length: aggregation itself triggers aberrant interactions.

    abstract::Huntington's disease (HD) is caused by the expansion mutation above a length threshold of a polyglutamine (polyQ) stretch in the huntingtin (Htt) protein. Mutant Htt (mHtt) pathogenicity is proposed to rely on its malfunction and propensity to misfold and aggregate. Htt has scaffolding properties and has been reported...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Davranche A,Aviolat H,Zeder-Lutz G,Busso D,Altschuh D,Trottier Y,Klein FA

    更新日期:2011-07-15 00:00:00

  • Disruption of the neurexin 1 gene is associated with schizophrenia.

    abstract::Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European popula...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Rujescu D,Ingason A,Cichon S,Pietiläinen OP,Barnes MR,Toulopoulou T,Picchioni M,Vassos E,Ettinger U,Bramon E,Murray R,Ruggeri M,Tosato S,Bonetto C,Steinberg S,Sigurdsson E,Sigmundsson T,Petursson H,Gylfason A,Olason

    更新日期:2009-03-01 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


    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

  • Analysis of the steroidogenic acute regulatory protein (StAR) gene in Japanese patients with congenital lipoid adrenal hyperplasia.

    abstract::Genomic DNA from 19 Japanese patients with congenital lipoid adrenal hyperplasia (lipoid CAH) representing 16 different families was examined to identify the genetic alterations of steroidogenic acute regulatory protein (StAR). Ten of 19 patients had a 46,XX karyotype and nine had a 46,XY karyotype. Six of the 46,XX p...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Nakae J,Tajima T,Sugawara T,Arakane F,Hanaki K,Hotsubo T,Igarashi N,Igarashi Y,Ishii T,Koda N,Kondo T,Kohno H,Nakagawa Y,Tachibana K,Takeshima Y,Tsubouchi K,Strauss JF 3rd,Fujieda K

    更新日期:1997-04-01 00:00:00

  • Mitofusin 2 is necessary for striatal axonal projections of midbrain dopamine neurons.

    abstract::Mitochondrial dysfunction is implicated in aging and degenerative disorders such as Parkinson's disease (PD). Continuous fission and fusion of mitochondria shapes their morphology and is essential to maintain oxidative phosphorylation. Loss-of-function mutations in PTEN-induced kinase1 (PINK1) or Parkin cause a recess...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Lee S,Sterky FH,Mourier A,Terzioglu M,Cullheim S,Olson L,Larsson NG

    更新日期:2012-11-15 00:00:00

  • Preimplantation prevention of X-linked disease: reliable and rapid sex determination of single human cells by restriction analysis of simultaneously amplified ZFX and ZFY sequences.

    abstract::In vitro fertilization (IVF), blastomere biopsy of the 6-8 cell embryo, and single cell DNA diagnosis allows couples at risk of transmitting an X-linked or autosomal disease to start a pregnancy knowing their child will not be affected. We present a quick and reliable nested PCR strategy for sex determination at the s...

    journal_title:Human molecular genetics

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Chong SS,Kristjansson K,Cota J,Handyside AH,Hughes MR

    更新日期:1993-08-01 00:00:00

  • The BRC repeats are conserved in mammalian BRCA2 proteins.

    abstract::The breast cancer susceptibility gene BRCA2 encodes a protein of 3418 amino acids which does not exhibit substantial sequence similarity to any other protein in the public databases. A dot matrix comparison of BRCA2 with itself revealed an eight times repeated motif in the segment of the protein encoded by exon 11. As...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Bignell G,Micklem G,Stratton MR,Ashworth A,Wooster R

    更新日期:1997-01-01 00:00:00

  • A transcription map of the region containing the Huntington disease gene.

    abstract::A transcription map of the Huntington disease gene region was generated by a direct cDNA selection strategy using genomic DNA from the 4p16.3 region surrounding the D4S95 and D4S127 loci. A total of 58 cDNA fragments were obtained from cDNAs derived from fetal brain, frontal cortex, liver and bone marrow following hyb...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Rommens JM,Lin B,Hutchinson GB,Andrew SE,Goldberg YP,Glaves ML,Graham R,Lai V,McArthur J,Nasir J

    更新日期:1993-07-01 00:00:00

  • A dinucleotide mutation in the endothelin-B receptor gene is associated with lethal white foal syndrome (LWFS); a horse variant of Hirschsprung disease.

    abstract::Lethal white foal syndrome (LWFS) is a congenital anomaly of horses characterized by a white coat colour and aganglionosis of the bowel, which is similar to Hirschsprung disease (HSCR). We decided to investigate possible mutations of the endothelin-B receptor gene ( EDNRB ) in LWFS as recent studies in mutant rodents ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Yang GC,Croaker D,Zhang AL,Manglick P,Cartmill T,Cass D

    更新日期:1998-06-01 00:00:00

  • Biallelic expression of the IGF2 gene in human breast disease.

    abstract::We examined the imprinting status of the insulin-like growth factor II gene (IGF2) in a series of 20 human breast disease samples to determine if disrupted imprinting (as evidenced by biallelic expression), was a demonstrable mechanism of altered gene expression. These samples included benign (n = 7) and malignant bre...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: McCann AH,Miller N,O'Meara A,Pedersen I,Keogh K,Gorey T,Dervan PA

    更新日期:1996-08-01 00:00:00

  • Paternal monoallelic expression of PEG3 in the human placenta.

    abstract::Genomic imprinting is the phenomenon whereby mono-allelic expression of certain genes occurs depending on their parental origin. The observation that imprinting only occurs in placental mammals has led to the suggestion that it may play a role in this form of reproduction. In the present study we have investigated the...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Hiby SE,Lough M,Keverne EB,Surani MA,Loke YW,King A

    更新日期:2001-05-01 00:00:00

  • Neural cell recognition molecule L1: relating biological complexity to human disease mutations.

    abstract::Human single gene disorders that affect the nervous system provide a host of natural mutations that can be deployed in the quest to understand its development and function. A paradigm for this approach is the study of disorders caused by mutations in the gene for the neural cell recognition molecule L1. L1 is the foun...

    journal_title:Human molecular genetics

    pub_type: 杂志文章,评审


    authors: Kenwrick S,Watkins A,De Angelis E

    更新日期:2000-04-12 00:00:00

  • Common variants at VRK2 and TCF4 conferring risk of schizophrenia.

    abstract::Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章,meta分析


    authors: Steinberg S,de Jong S,Irish Schizophrenia Genomics Consortium.,Andreassen OA,Werge T,Børglum AD,Mors O,Mortensen PB,Gustafsson O,Costas J,Pietiläinen OP,Demontis D,Papiol S,Huttenlocher J,Mattheisen M,Breuer R,Vassos E,

    更新日期:2011-10-15 00:00:00

  • Drug repositioning as a therapeutic strategy for neurodegenerations associated with OPA1 mutations.

    abstract::OPA1 mutations are the major cause of dominant optic atrophy (DOA) and the syndromic form DOA plus, pathologies for which there is no established cure. We used a 'drug repurposing' approach to identify FDA-approved molecules able to rescue the mitochondrial dysfunctions induced by OPA1 mutations. We screened two diffe...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Aleo SJ,Del Dotto V,Fogazza M,Maresca A,Lodi T,Goffrini P,Ghelli A,Rugolo M,Carelli V,Baruffini E,Zanna C

    更新日期:2021-01-21 00:00:00

  • Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region.

    abstract::An association between the 19q13.2 chromosomal region and Alzheimer's disease (AD) has been reported in AD families and for sporadic AD. Recent observations provide evidence that the epsilon 4 allele of the apolipoprotein E gene (APOE), located in this region, is a risk factor for late-onset AD. Within this region, ot...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Chartier-Harlin MC,Parfitt M,Legrain S,Pérez-Tur J,Brousseau T,Evans A,Berr C,Vidal O,Roques P,Gourlet V

    更新日期:1994-04-01 00:00:00

  • Molecular genetic investigations identify new clinical phenotypes associated with BCS1L-related mitochondrial disease.

    abstract::BCS1L encodes a homolog of the Saccharomyces cerevisiae bcs1 protein, which has a known role in the assembly of Complex III of the mitochondrial respiratory chain. Phenotypes reported in association with pathogenic BCS1L variants include growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis an...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Oláhová M,Ceccatelli Berti C,Collier JJ,Alston CL,Jameson E,Jones SA,Edwards N,He L,Chinnery PF,Horvath R,Goffrini P,Taylor RW,Sayer JA

    更新日期:2019-11-15 00:00:00

  • In vitro-differentiated neural cell cultures progress towards donor-identical brain tissue.

    abstract::Multiple research groups have observed neuropathological phenotypes and molecular symptoms in vitro using induced pluripotent stem cell (iPSC)-derived neural cell cultures (i.e. patient-specific neurons and glia). However, the global differences/similarities that may exist between in vitro neural cells and their tissu...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Hjelm BE,Salhia B,Kurdoglu A,Szelinger S,Reiman RA,Sue LI,Beach TG,Huentelman MJ,Craig DW

    更新日期:2013-09-01 00:00:00