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Publications

Total: 69 results

  • Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia

    March 21, 2024
    Author(s): Salome Funes,Jonathan Jung,Del Hayden Gadd,Michelle Mosqueda,Jianjun Zhong,None Shankaracharya,Matthew Unger,Karly Stallworth,Debra Cameron,Melissa S Rotunno,Pepper Dawes,Megan Fowler-Magaw,Pamela J K...
    Source: Nature communications
    Microglia play a pivotal role in neurodegenerative disease pathogenesis, but the mechanisms underlying microglia dysfunction and toxicity remain to be elucidated. To investigate the effect of neurodeg...

  • Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import

    August 16, 2023
    Author(s): Jacob R Mann,Elizabeth D McKenna,Darilang Mawrie,Vasileios Papakis,Francesco Alessandrini,Eric N Anderson,Ryan Mayers,Hannah E Ball,Evan Kaspi,Katherine Lubinski,Desiree M Baron,Liana Tellez,John E La...
    Source: Science advances
    Loss-of-function variants in NIMA-related kinase 1 (NEK1) constitute a major genetic cause of amyotrophic lateral sclerosis (ALS), accounting for 2 to 3% of all cases. However, how NEK1 mutations caus...

  • Genome-wide structural variant analysis identifies risk loci for non-Alzheimer's dementias

    June 30, 2023
    Author(s): Karri Kaivola,Ruth Chia,Jinhui Ding,Memoona Rasheed,Masashi Fujita,Vilas Menon,Ronald L Walton,Ryan L Collins,Kimberley Billingsley,Harrison Brand,Michael Talkowski,Xuefang Zhao,Ramita Dewan,Ali Stark...
    Source: Cell genomics
    We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer's dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/am...

  • Genetic variability in sporadic amyotrophic lateral sclerosis

    April 12, 2023
    Author(s): Sien Hilde Van Daele,Matthieu Moisse,Joke J F A van Vugt,Ramona A J Zwamborn,Rick van der Spek,Wouter van Rheenen,Kristel Van Eijk,Kevin Kenna,Philippe Corcia,Patrick Vourc'h,Philippe Couratier,Orla H...
    Source: Brain : a journal of neurology
    With the advent of gene therapies for amyotrophic lateral sclerosis (ALS), there is a surge in gene testing for this disease. Although there is ample experience with gene testing for C9orf72, SOD1, FU...

  • Amyotrophic lateral sclerosis: translating genetic discoveries into therapies

    April 06, 2023
    Author(s): Fulya Akçimen,Elia R Lopez,John E Landers,Avindra Nath,Adriano Chiò,Ruth Chia,Bryan J Traynor
    Source: Nature reviews. Genetics
    Recent advances in sequencing technologies and collaborative efforts have led to substantial progress in identifying the genetic causes of amyotrophic lateral sclerosis (ALS). This momentum has, in tu...

  • Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival

    March 20, 2023
    Author(s): Brett N Adey,Johnathan Cooper-Knock,Ahmad Al Khleifat,Isabella Fogh,Philip van Damme,Philippe Corcia,Philippe Couratier,Orla Hardiman,Russell McLaughlin,Marc Gotkine,Vivian Drory,Vincenzo Silani,Nicol...
    Source: Frontiers in cellular neuroscience
    Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role i...

  • Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data

    January 02, 2023
    Author(s): Ahmad Al Khleifat,Alfredo Iacoangeli,Ashley R Jones,Joke J F A van Vugt,Matthieu Moisse,Aleksey Shatunov,Ramona A J Zwamborn,Rick A A van der Spek,Johnathan Cooper-Knock,Simon Topp,Wouter van Rheenen,...
    Source: Frontiers in cellular neuroscience
    BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to progressive weakness of voluntary muscles, with de...

  • The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration

    November 13, 2022
    Author(s): Sarah Opie-Martin,Alfredo Iacoangeli,Simon D Topp,Olubunmi Abel,Keith Mayl,Puja R Mehta,Aleksey Shatunov,Isabella Fogh,Harry Bowles,Naomi Limbachiya,Thomas P Spargo,Ahmad Al-Khleifat,Kelly L Williams,...
    Source: Nature communications
    Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this...

  • ATXN2 intermediate expansions in amyotrophic lateral sclerosis

    May 06, 2022
    Author(s): Jonathan D Glass,Ramita Dewan,Jinhui Ding,J Raphael Gibbs,Clifton Dalgard,Pamela J Keagle,None Shankaracharya,Alberto García-Redondo,Bryan J Traynor,Ruth Chia,John E Landers
    Source: Brain : a journal of neurology
    Intermediate CAG (polyQ) expansions in the gene ataxin-2 (ATXN2) are now recognized as a risk factor for amyotrophic lateral sclerosis. The threshold for increased risk is not yet firmly established, ...

  • ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function

    April 06, 2022
    Author(s): Desiree M Baron,Adam R Fenton,Sara Saez-Atienzar,Anthony Giampetruzzi,Aparna Sreeram,None Shankaracharya,Pamela J Keagle,Victoria R Doocy,Nathan J Smith,Eric W Danielson,Megan Andresano,Mary C McCorma...
    Source: Cell reports
    Understanding the pathogenic mechanisms of disease mutations is critical to advancing treatments. ALS-associated mutations in the gene encoding the microtubule motor KIF5A result in skipping of exon 2...

  • Homozygous might be hemizygous: CRISPR/Cas9 editing in iPSCs results in detrimental on-target defects that escape standard quality controls

    March 11, 2022
    Author(s): Dina Simkin,Vasileios Papakis,Bernabe I Bustos,Christina M Ambrosi,Steven J Ryan,Valeriya Baru,Luis A Williams,Graham T Dempsey,Owen B McManus,John E Landers,Steven J Lubbe,Alfred L George,Evangelos K...
    Source: Stem cell reports
    The ability to precisely edit the genome of human induced pluripotent stem cell (iPSC) lines using CRISPR/Cas9 has enabled the development of cellular models that can address genotype to phenotype rel...

  • Role of Lysosomal Gene Variants in Modulating GBA-Associated Parkinson's Disease Risk

    March 09, 2022
    Author(s): Letizia Straniero,Valeria Rimoldi,Edoardo Monfrini,Salvatore Bonvegna,Giada Melistaccio,Julie Lake,Giulia Soldà,Massimo Aureli,None Shankaracharya,Pamela Keagle,Tatiana Foroud,John E Landers,Cornelis ...
    Source: Movement disorders : official journal of the Movement Disorder Society
    CONCLUSION: The identification of genetic lesions in lysosomal genes increasing PD risk may have important implications in terms of patient stratification for future therapeutic trials. © 2022 The Aut...

  • Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS

    February 23, 2022
    Author(s): Paul J Hop,Ramona A J Zwamborn,Eilis Hannon,Gemma L Shireby,Marta F Nabais,Emma M Walker,Wouter van Rheenen,Joke J F A van Vugt,Annelot M Dekker,Henk-Jan Westeneng,Gijs H P Tazelaar,Kristel R van Eijk...
    Source: Science translational medicine
    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and diseas...

  • Author Correction: Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

    February 01, 2022
    Author(s): Wouter van Rheenen,Rick A A van der Spek,Mark K Bakker,Joke J F A van Vugt,Paul J Hop,Ramona A J Zwamborn,Niek de Klein,Harm-Jan Westra,Olivier B Bakker,Patrick Deelen,Gemma Shireby,Eilis Hannon,Matth...
    Source: Nature genetics
    No abstract

  • Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis

    January 29, 2022
    Author(s): Ahmad Al Khleifat,Alfredo Iacoangeli,Joke J F A van Vugt,Harry Bowles,Matthieu Moisse,Ramona A J Zwamborn,Rick A A van der Spek,Aleksey Shatunov,Johnathan Cooper-Knock,Simon Topp,Ross Byrne,Cinzia Gel...
    Source: NPJ genomic medicine
    There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in comm...

  • Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

    December 07, 2021
    Author(s): Wouter van Rheenen,Rick A A van der Spek,Mark K Bakker,Joke J F A van Vugt,Paul J Hop,Ramona A J Zwamborn,Niek de Klein,Harm-Jan Westra,Olivier B Bakker,Patrick Deelen,Gemma Shireby,Eilis Hannon,Matth...
    Source: Nature genetics
    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry geno...

  • Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

    August 30, 2021
    Author(s): Janel O Johnson,Ruth Chia,Danny E Miller,Rachel Li,Ravindran Kumaran,Yevgeniya Abramzon,Nada Alahmady,Alan E Renton,Simon D Topp,J Raphael Gibbs,Mark R Cookson,Marya S Sabir,Clifton L Dalgard,Claire T...
    Source: JAMA neurology
    CONCLUSIONS AND RELEVANCE: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

  • Novel TUBA4A Variant Associated With Familial Frontotemporal Dementia

    June 25, 2021
    Author(s): Merel O Mol,Tsz H Wong,Shamiram Melhem,Sreya Basu,Riccardo Viscusi,Niels Galjart,Annemieke J M Rozemuller,Claudia Fallini,John E Landers,Laura Donker Kaat,Harro Seelaar,Jeroen G J van Rooij,John C van...
    Source: Neurology. Genetics
    CONCLUSIONS: Our findings support the role of TUBA4A variants as rare genetic cause of familial FTD.

  • Interactions between ALS-linked FUS and nucleoporins are associated with defects in the nucleocytoplasmic transport pathway

    June 01, 2021
    Author(s): Yen-Chen Lin,Meenakshi Sundaram Kumar,Nandini Ramesh,Eric N Anderson,Aivi T Nguyen,Boram Kim,Simon Cheung,Justin A McDonough,William C Skarnes,Rodrigo Lopez-Gonzalez,John E Landers,Nicolas L Fawzi,Ian...
    Source: Nature neuroscience
    Nucleocytoplasmic transport (NCT) decline occurs with aging and neurodegeneration. Here, we investigated the NCT pathway in models of amyotrophic lateral sclerosis-fused in sarcoma (ALS-FUS). Expressi...

  • Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder

    May 08, 2021
    Author(s): Sukhleen Kour,Deepa S Rajan,Tyler R Fortuna,Eric N Anderson,Caroline Ward,Youngha Lee,Sangmoon Lee,Yong Beom Shin,Jong-Hee Chae,Murim Choi,Karine Siquier,Vincent Cantagrel,Jeanne Amiel,Elliot S Stoler...
    Source: Nature communications
    GEMIN5, an RNA-binding protein is essential for assembly of the survival motor neuron (SMN) protein complex and facilitates the formation of small nuclear ribonucleoproteins (snRNPs), the building blo...

  • Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types

    February 01, 2021
    Author(s): Sara Saez-Atienzar,Sara Bandres-Ciga,Rebekah G Langston,Jonggeol J Kim,Shing Wan Choi,Regina H Reynolds,International ALS Genomics Consortium,ITALSGEN,Yevgeniya Abramzon,Ramita Dewan,Sarah Ahmed,John ...
    Source: Science advances
    Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genom...

  • The Effect of SMN Gene Dosage on ALS Risk and Disease Severity

    January 03, 2021
    Author(s): Matthieu Moisse,Ramona A J Zwamborn,Joke van Vugt,Rick van der Spek,Wouter van Rheenen,Brendan Kenna,Kristel Van Eijk,Kevin Kenna,Philippe Corcia,Philippe Couratier,Patrick Vourc'h,Orla Hardiman,Russe...
    Source: Annals of neurology
    OBJECTIVE: The role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given tha...

  • Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

    November 26, 2020
    Author(s): Ramita Dewan,Ruth Chia,Jinhui Ding,Richard A Hickman,Thor D Stein,Yevgeniya Abramzon,Sarah Ahmed,Marya S Sabir,Makayla K Portley,Arianna Tucci,Kristina Ibáñez,F N U Shankaracharya,Pamela Keagle,Giacom...
    Source: Neuron
    We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patien...

  • ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization

    September 21, 2020
    Author(s): Gijs H P Tazelaar,Steven Boeynaems,Mathias De Decker,Joke J F A van Vugt,Lindy Kool,H Stephan Goedee,Russell L McLaughlin,William Sproviero,Alfredo Iacoangeli,Matthieu Moisse,Maarten Jacquemyn,Dirk Da...
    Source: Brain communications
    Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated w...

  • CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral sclerosis

    March 19, 2020
    Author(s): Carol Dobson-Stone,Marianne Hallupp,Hamideh Shahheydari,Audrey M G Ragagnin,Zac Chatterton,Francine Carew-Jones,Claire E Shepherd,Holly Stefen,Esmeralda Paric,Thomas Fath,Elizabeth M Thompson,Peter Bl...
    Source: Brain : a journal of neurology
    Frontotemporal dementia and amyotrophic lateral sclerosis are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p...

  • Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology

    December 20, 2019
    Author(s): Irit Reichenstein,Chen Eitan,Sandra Diaz-Garcia,Guy Haim,Iddo Magen,Aviad Siany,Mariah L Hoye,Natali Rivkin,Tsviya Olender,Beata Toth,Revital Ravid,Amitai D Mandelbaum,Eran Yanowski,Jing Liang,Jeffrey...
    Source: Science translational medicine
    Motor neuron-specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. H...

  • Ly6a Differential Expression in Blood-Brain Barrier Is Responsible for Strain Specific Central Nervous System Transduction Profile of AAV-PHP.B

    November 08, 2019
    Author(s): Ana Rita Batista,Oliver D King,Christopher P Reardon,Crystal Davis,None Shankaracharya,Vivek Philip,Heather Gray-Edwards,Neil Aronin,Cathleen Lutz,John Landers,Miguel Sena-Esteves
    Source: Human gene therapy
    Adeno-associated virus (AAV) gene therapy for neurological diseases was revolutionized by the discovery that AAV9 crosses the blood-brain barrier (BBB) after systemic administration. Transformative re...

  • Modulation of actin polymerization affects nucleocytoplasmic transport in multiple forms of amyotrophic lateral sclerosis

    August 25, 2019
    Author(s): Anthony Giampetruzzi,Eric W Danielson,Valentina Gumina,Maryangel Jeon,Sivakumar Boopathy,Robert H Brown,Antonia Ratti,John E Landers,Claudia Fallini
    Source: Nature communications
    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown etiology. Although defects in nucleocytoplasmic transport (NCT) may be central to the pathogenesis of ALS and other ...

  • TDP-43 and NOVA-1 RNA-binding proteins as competitive splicing regulators of the schizophrenia-associated TNIK gene

    August 06, 2019
    Author(s): Valentina Gumina,Claudia Colombrita,Claudia Fallini,Patrizia Bossolasco,Anna Maria Maraschi,John E Landers,Vincenzo Silani,Antonia Ratti
    Source: Biochimica et biophysica acta. Gene regulatory mechanisms
    The RNA-binding protein TDP-43, associated to amyotrophic lateral sclerosis and frontotemporal dementia, regulates the alternative splicing of several genes, including the skipping of TNIK exon 15. TN...

  • The RNA-binding protein FUS/TLS undergoes calcium-mediated nuclear egress during excitotoxic stress and is required for GRIA2 mRNA processing

    May 17, 2019
    Author(s): Maeve Tischbein,Desiree M Baron,Yen-Chen Lin,Katherine V Gall,John E Landers,Claudia Fallini,Daryl A Bosco
    Source: The Journal of biological chemistry
    Excitotoxic levels of glutamate represent a physiological stress that is strongly linked to amyotrophic lateral sclerosis (ALS) and other neurological disorders. Emerging evidence indicates a role for...

  • Rare variants in MYH15 modify amyotrophic lateral sclerosis risk

    April 16, 2019
    Author(s): Hyerim Kim,Junghwa Lim,Han Bao,Bin Jiao,Se Min Canon,Michael P Epstein,Keqin Xu,Jie Jiang,Janani Parameswaran,Yingjie Li,Kenneth H Moberg,John E Landers,Christina Fournier,Emily G Allen,Jonathan D Gla...
    Source: Human molecular genetics
    Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive muscular atrophy and respiratory failure. The G4C2 repeat expansion in the C9orf72 gene is the most pr...

  • Mutations in the Glycosyltransferase Domain of GLT8D1 Are Associated with Familial Amyotrophic Lateral Sclerosis

    February 28, 2019
    Author(s): Johnathan Cooper-Knock,Tobias Moll,Tennore Ramesh,Lydia Castelli,Alexander Beer,Henry Robins,Ian Fox,Isabell Niedermoser,Philip Van Damme,Matthieu Moisse,Wim Robberecht,Orla Hardiman,Monica P Panades,...
    Source: Cell reports
    Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder without effective neuroprotective therapy. Known genetic variants impair pathways, including RNA processing, axonal transport...

  • Quantitative proteomics identifies proteins that resist translational repression and become dysregulated in ALS-FUS

    February 27, 2019
    Author(s): Desiree M Baron,Tyler Matheny,Yen-Chen Lin,John D Leszyk,Kevin Kenna,Katherine V Gall,David P Santos,Maeve Tischbein,Salome Funes,Lawrence J Hayward,Evangelos Kiskinis,John E Landers,Roy Parker,Scott ...
    Source: Human molecular genetics
    Aberrant translational repression is a feature of multiple neurodegenerative diseases. The association between disease-linked proteins and stress granules further implicates impaired stress responses ...

  • Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort

    October 22, 2018
    Author(s): Gijs H P Tazelaar,Annelot M Dekker,Joke J F A van Vugt,Rick A van der Spek,Henk-Jan Westeneng,Lindy J B G Kool,Kevin P Kenna,Wouter van Rheenen,Sara L Pulit,Russell L McLaughlin,William Sproviero,Alfr...
    Source: Neurobiology of aging
    NIPA1 (nonimprinted in Prader-Willi/Angelman syndrome 1) mutations are known to cause hereditary spastic paraplegia type 6, a neurodegenerative disease that phenotypically overlaps to some extent with...

  • ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function

    July 24, 2018
    Author(s): Martina de Majo,Simon D Topp,Bradley N Smith,Agnes L Nishimura,Han-Jou Chen,Athina Soragia Gkazi,Jack Miller,Chun Hao Wong,Caroline Vance,Frank Baas,Anneloor L M A Ten Asbroek,Kevin P Kenna,Nicola Tic...
    Source: Neurobiology of aging
    Mutations in TANK binding kinase 1 (TBK1) have been linked to amyotrophic lateral sclerosis. Some TBK1 variants are nonsense and are predicted to cause disease through haploinsufficiency; however, man...

  • Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

    March 24, 2018
    Author(s): Aude Nicolas,Kevin P Kenna,Alan E Renton,Nicola Ticozzi,Faraz Faghri,Ruth Chia,Janice A Dominov,Brendan J Kenna,Mike A Nalls,Pamela Keagle,Alberto M Rivera,Wouter van Rheenen,Natalie A Murphy,Joke J F...
    Source: Neuron
    To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we p...

  • The LRRK2 Variant E193K Prevents Mitochondrial Fission Upon MPP+ Treatment by Altering LRRK2 Binding to DRP1

    March 16, 2018
    Author(s): Maria Perez Carrion,Francesca Pischedda,Alice Biosa,Isabella Russo,Letizia Straniero,Laura Civiero,Marianna Guida,Christian J Gloeckner,Nicola Ticozzi,Cinzia Tiloca,Claudio Mariani,Gianni Pezzoli,Stef...
    Source: Frontiers in molecular neuroscience
    Mutations in leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial and sporadic Parkinson's disease (PD). LRRK2 is a complex protein that consists of multiple domains, including 13 pu...

  • Transcription factor Pebbled/RREB1 regulates injury-induced axon degeneration

    January 04, 2018
    Author(s): Jonathan E Farley,Thomas C Burdett,Romina Barria,Lukas J Neukomm,Kevin P Kenna,John E Landers,Marc R Freeman
    Source: Proceedings of the National Academy of Sciences of the United States of America
    Genetic studies of Wallerian degeneration have led to the identification of signaling molecules (e.g., dSarm/Sarm1, Axundead, and Highwire) that function locally in axons to drive degeneration. Here w...

  • Reconsidering the causality of TIA1 mutations in ALS

    December 14, 2017
    Author(s): Rick A van der Spek,Wouter van Rheenen,Sara L Pulit,Kevin P Kenna,Nicola Ticozzi,Maarten Kooyman,Russell L Mclaughlin,Matthieu Moisse,Kristel R van Eijk,Joke J F A van Vugt,Alfredo Iacoangeli,Peter An...
    Source: Amyotrophic lateral sclerosis & frontotemporal degeneration
    No abstract

  • The role of de novo mutations in the development of amyotrophic lateral sclerosis

    July 18, 2017
    Author(s): Perry T C van Doormaal,Nicola Ticozzi,Jochen H Weishaupt,Kevin Kenna,Frank P Diekstra,Federico Verde,Peter M Andersen,Annelot M Dekker,Cinzia Tiloca,Nicolai Marroquin,Daniel J Overste,Viviana Pensato,...
    Source: Human mutation
    The genetic basis combined with the sporadic occurrence of amyotrophic lateral sclerosis (ALS) suggests a role of de novo mutations in disease pathogenesis. Previous studies provided some evidence for...

  • Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis

    May 05, 2017
    Author(s): Bradley N Smith,Simon D Topp,Claudia Fallini,Hideki Shibata,Han-Jou Chen,Claire Troakes,Andrew King,Nicola Ticozzi,Kevin P Kenna,Athina Soragia-Gkazi,Jack W Miller,Akane Sato,Diana Marques Dias,Maryan...
    Source: Science translational medicine
    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. We screened 751 familial ALS patient whole-exome sequences and identified six mutations including p.D40G in the ANXA11 gene i...

  • A Drosophila model of ALS reveals a partial loss of function of causative human PFN1 mutants

    April 06, 2017
    Author(s): Chi-Hong Wu,Anthony Giampetruzzi,Helene Tran,Claudia Fallini,Fen-Biao Gao,John E Landers
    Source: Human molecular genetics
    Mutations in the profilin 1 (PFN1) gene are causative for familial amyotrophic lateral sclerosis (fALS). However, it is still not fully understood how these mutations lead to neurodegeneration. To add...

  • ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation

    March 10, 2017
    Author(s): Reddy Ranjith K Sama,Claudia Fallini,Rodolfo Gatto,Jeanne E McKeon,Yuyu Song,Melissa S Rotunno,Saul Penaranda,Izrail Abdurakhmanov,John E Landers,Gerardo Morfini,Scott T Brady,Daryl A Bosco
    Source: Scientific reports
    Mutations in Fused in Sarcoma/Translocated in Liposarcoma (FUS) cause familial forms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive axonal degeneratio...

  • Mutant PFN1 causes ALS phenotypes and progressive motor neuron degeneration in mice by a gain of toxicity

    September 30, 2016
    Author(s): Chunxing Yang,Eric W Danielson,Tao Qiao,Jake Metterville,Robert H Brown,John E Landers,Zuoshang Xu
    Source: Proceedings of the National Academy of Sciences of the United States of America
    Mutations in the profilin 1 (PFN1) gene cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease caused by the loss of motor neurons leading to paralysis and eventually death. PFN1 is a ...

  • Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population

    August 05, 2016
    Author(s): Mfon E Umoh,Christina Fournier,Yingjie Li,Meraida Polak,Latoya Shaw,John E Landers,William Hu,Marla Gearing,Jonathan D Glass
    Source: Neurology
    CONCLUSIONS: Comparing the C9orf72 ALS population to the general ALS population, there were no differences in race, age at onset, or proportion of patients with bulbar onset disease. Differences ident...

  • Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

    July 26, 2016
    Author(s): Wouter van Rheenen,Aleksey Shatunov,Annelot M Dekker,Russell L McLaughlin,Frank P Diekstra,Sara L Pulit,Rick A A van der Spek,Urmo Võsa,Simone de Jong,Matthew R Robinson,Jian Yang,Isabella Fogh,Perry ...
    Source: Nature genetics
    To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS an...

  • NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

    July 26, 2016
    Author(s): Kevin P Kenna,Perry T C van Doormaal,Annelot M Dekker,Nicola Ticozzi,Brendan J Kenna,Frank P Diekstra,Wouter van Rheenen,Kristel R van Eijk,Ashley R Jones,Pamela Keagle,Aleksey Shatunov,William Sprovi...
    Source: Nature genetics
    To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strat...

  • SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models

    July 19, 2016
    Author(s): Luisa Quinti,Malcolm Casale,Sébastien Moniot,Teresa F Pais,Michael J Van Kanegan,Linda S Kaltenbach,Judit Pallos,Ryan G Lim,Sharadha Dayalan Naidu,Heike Runne,Lisa Meisel,Nazifa Abdul Rauf,Dmitriy Ley...
    Source: Cell chemical biology
    There are currently no disease-modifying therapies for the neurodegenerative disorder Huntington's disease (HD). This study identified novel thiazole-containing inhibitors of the deacetylase sirtuin-2...

  • Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis

    June 01, 2016
    Author(s): Isabella Fogh,Kuang Lin,Cinzia Tiloca,James Rooney,Cinzia Gellera,Frank P Diekstra,Antonia Ratti,Aleksey Shatunov,Michael A van Es,Petroula Proitsi,Ashley Jones,William Sproviero,Adriano Chiò,Russell ...
    Source: JAMA neurology
    CONCLUSIONS AND RELEVANCE: This GWAS robustly identified 2 loci at genome-wide levels of significance that influence survival in patients with ALS. Because ALS is a rare disease and prevention is not ...

  • CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

    April 16, 2016
    Author(s): Kelly L Williams,Simon Topp,Shu Yang,Bradley Smith,Jennifer A Fifita,Sadaf T Warraich,Katharine Y Zhang,Natalie Farrawell,Caroline Vance,Xun Hu,Alessandra Chesi,Claire S Leblond,Albert Lee,Stephanie L...
    Source: Nature communications
    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquiti...

  • Structural basis for mutation-induced destabilization of profilin 1 in ALS

    June 10, 2015
    Author(s): Sivakumar Boopathy,Tania V Silvas,Maeve Tischbein,Silvia Jansen,Shivender M Shandilya,Jill A Zitzewitz,John E Landers,Bruce L Goode,Celia A Schiffer,Daryl A Bosco
    Source: Proceedings of the National Academy of Sciences of the United States of America
    Mutations in profilin 1 (PFN1) are associated with amyotrophic lateral sclerosis (ALS); however, the pathological mechanism of PFN1 in this fatal disease is unknown. We demonstrate that ALS-linked mut...

  • Identification of rare protein disulfide isomerase gene variants in amyotrophic lateral sclerosis patients

    April 28, 2015
    Author(s): Paloma Gonzalez-Perez,Ute Woehlbier,Ru-Ju Chian,Peter Sapp,Guy A Rouleau,Claire S Leblond,Hussein Daoud,Patrick A Dion,John E Landers,Claudio Hetz,Robert H Brown
    Source: Gene
    Disruption of endoplasmic reticulum (ER) proteostasis is a salient feature of amyotrophic lateral sclerosis (ALS). Upregulation of ER foldases of the protein disulfide isomerase (PDI) family has been ...

  • Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

    February 21, 2015
    Author(s): Elizabeth T Cirulli,Brittany N Lasseigne,Slavé Petrovski,Peter C Sapp,Patrick A Dion,Claire S Leblond,Julien Couthouis,Yi-Fan Lu,Quanli Wang,Brian J Krueger,Zhong Ren,Jonathan Keebler,Yujun Han,Shawn ...
    Source: Science (New York, N.Y.)
    Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of gene...

  • The distinct genetic pattern of ALS in Turkey and novel mutations

    February 16, 2015
    Author(s): Aslıhan Özoğuz,Özgün Uyan,Güneş Birdal,Ceren Iskender,Ece Kartal,Suna Lahut,Özgür Ömür,Zeynep Sena Agim,Aslı Gündoğdu Eken,Nesli Ece Sen,Pınar Kavak,Ceren Saygı,Peter C Sapp,Pamela Keagle,Yeşim Parman...
    Source: Neurobiology of aging
    The frequency of amyotrophic lateral sclerosis (ALS) mutations has been extensively investigated in several populations; however, a systematic analysis in Turkish cases has not been reported so far. I...

  • A loss of FUS/TLS function leads to impaired cellular proliferation

    December 16, 2014
    Author(s): C L Ward,K J Boggio,B N Johnson,J B Boyd,S Douthwright,S A Shaffer,J E Landers,M A Glicksman,D A Bosco
    Source: Cell death & disease
    Fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS) is a multifunctional RNA/DNA-binding protein that is pathologically associated with cancer and neurodegeneration. To gain insight into the...

  • Novel mutations support a role for Profilin 1 in the pathogenesis of ALS

    December 16, 2014
    Author(s): Bradley N Smith,Caroline Vance,Emma L Scotter,Claire Troakes,Chun Hao Wong,Simon Topp,Satomi Maekawa,Andrew King,Jacqueline C Mitchell,Karan Lund,Ammar Al-Chalabi,Nicola Ticozzi,Vincenzo Silani,Peter ...
    Source: Neurobiology of aging
    Mutations in the gene encoding profilin 1 (PFN1) have recently been shown to cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. We sequenced the PFN1 gene in a cohort of AL...

  • Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS

    November 07, 2014
    Author(s): Bradley N Smith,Nicola Ticozzi,Claudia Fallini,Athina Soragia Gkazi,Simon Topp,Kevin P Kenna,Emma L Scotter,Jason Kost,Pamela Keagle,Jack W Miller,Daniela Calini,Caroline Vance,Eric W Danielson,Claire...
    Source: Neuron
    Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family m...

  • Analysis of the KIFAP3 gene in amyotrophic lateral sclerosis: a multicenter survival study

    May 20, 2014
    Author(s): Perry T C van Doormaal,Nicola Ticozzi,Cinzia Gellera,Antonia Ratti,Franco Taroni,Adriano Chiò,Andrea Calvo,Gabriele Mora,Gabriella Restagno,Bryan J Traynor,Anna Birve,Robin Lemmens,Michael A van Es,Ch...
    Source: Neurobiology of aging
    Sporadic amyotrophic lateral sclerosis is a multifactorial disease of environmental and genetic origin. In a previous large multicenter genome wide study, common genetic variation in the Kinesin-Assoc...

  • A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories

    April 08, 2014
    Author(s): Chizuru Akimoto,Alexander E Volk,Marka van Blitterswijk,Marleen Van den Broeck,Claire S Leblond,Serge Lumbroso,William Camu,Birgit Neitzel,Osamu Onodera,Wouter van Rheenen,Susana Pinto,Markus Weber,Br...
    Source: Journal of medical genetics
    CONCLUSIONS: Because of the wide range seen in genotyping results, we recommend using a combination of amplicon-length analysis and RP-PCR as a minimum in a research setting. We propose that Southern ...

  • Gender differences of mental health consumers accessing integrated primary and behavioral care

    May 09, 2013
    Author(s): H Gleason,M Hobart,L Bradley,J Landers,S Langenfeld,M Tonelli,M Kolodziej
    Source: Psychology, health & medicine
    Persons with severe mental illness and addiction are at higher risk for early morbidity and mortality than the general population, and are less likely to receive primary care and preventive health ser...

  • Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis

    July 18, 2012
    Author(s): Chi-Hong Wu,Claudia Fallini,Nicola Ticozzi,Pamela J Keagle,Peter C Sapp,Katarzyna Piotrowska,Patrick Lowe,Max Koppers,Diane McKenna-Yasek,Desiree M Baron,Jason E Kost,Paloma Gonzalez-Perez,Andrew D Fo...
    Source: Nature
    Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance ...

  • Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy

    May 31, 2011
    Author(s): Rachael M Duff,Valerie Tay,Peter Hackman,Gianina Ravenscroft,Catriona McLean,Paul Kennedy,Alina Steinbach,Wiebke Schöffler,Peter F M van der Ven,Dieter O Fürst,Jaeguen Song,Kristina Djinović-Carugo,Si...
    Source: American journal of human genetics
    Linkage analysis of the dominant distal myopathy we previously identified in a large Australian family demonstrated one significant linkage region located on chromosome 7 and encompassing 18.6 Mbp and...

  • Mutational analysis reveals the FUS homolog TAF15 as a candidate gene for familial amyotrophic lateral sclerosis

    March 26, 2011
    Author(s): N Ticozzi,C Vance,A L Leclerc,P Keagle,J D Glass,D McKenna-Yasek,P C Sapp,V Silani,D A Bosco,C E Shaw,R H Brown,J E Landers
    Source: American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
    FUS, EWS, and TAF15 belong to the TET family of structurally similar DNA/RNA-binding proteins. Mutations in the FUS gene have recently been discovered as a cause of familial amyotrophic lateral sclero...

  • Genetic determinants of amyotrophic lateral sclerosis as therapeutic targets

    October 15, 2010
    Author(s): Daryl A Bosco,John E Landers
    Source: CNS & neurological disorders drug targets
    Amyotrophic lateral sclerosis (ALS) is an incurable disease resulting from the deterioration of motor neurons. The onset of disease typically occurs in the fifth decade of life and progresses rapidly;...

  • Paraoxonase gene mutations in amyotrophic lateral sclerosis

    June 29, 2010
    Author(s): Nicola Ticozzi,Ashley Lyn LeClerc,Pamela J Keagle,Jonathan D Glass,Anne-Marie Wills,Marka van Blitterswijk,Daryl A Bosco,Ildefonso Rodriguez-Leyva,Cinzia Gellera,Antonia Ratti,Franco Taroni,Diane McKe...
    Source: Annals of neurology
    Three clustered, homologous paraoxonase genes (PON1, PON2, and PON3) have roles in preventing lipid oxidation and detoxifying organophosphates. Recent reports describe a genetic association between th...

  • RNA processing pathways in amyotrophic lateral sclerosis

    March 30, 2010
    Author(s): Marka van Blitterswijk,John E Landers
    Source: Neurogenetics
    RNA processing is a tightly regulated, highly complex pathway which includes RNA transcription, pre-mRNA splicing, editing, transportation, translation, and degradation of RNA. Over the past few years...

  • Mutational analysis of TARDBP in neurodegenerative diseases

    December 25, 2009
    Author(s): Nicola Ticozzi,Ashley Lyn LeClerc,Marka van Blitterswijk,Pamela Keagle,Diane M McKenna-Yasek,Peter C Sapp,Vincenzo Silani,Anne-Marie Wills,Robert H Brown,John E Landers
    Source: Neurobiology of aging
    Neurodegenerative diseases are often characterized by the presence of aggregates of misfolded proteins. TDP-43 is a major component of these aggregates in amyotrophic lateral sclerosis (ALS), but has ...

  • Analysis of FUS gene mutation in familial amyotrophic lateral sclerosis within an Italian cohort

    September 11, 2009
    Author(s): N Ticozzi,V Silani,A L LeClerc,P Keagle,C Gellera,A Ratti,F Taroni,T J Kwiatkowski,D M McKenna-Yasek,P C Sapp,R H Brown,J E Landers
    Source: Neurology
    CONCLUSIONS: Our results demonstrate that FUS mutations cause approximately 4% of familial amyotrophic lateral sclerosis cases in the Italian population.

  • A simple, bead-based approach for multi-SNP molecular haplotyping

    January 08, 2005
    Author(s): James D Hurley,Linda J Engle,Jesse T Davis,Adam M Welsh,John E Landers
    Source: Nucleic acids research
    Single nucleotide polymorphisms (SNPs) within a gene region have often been studied to determine their effect on phenotype. Although a single base pair change can produce a phenotypic change, phenotyp...