C9orf72 expansions in frontotemporal dementia and amyotrophic lateral sclerosis

Rohrer, Jonathan D.; Isaacs, Adrian M.; Mizielinska, Sarah; Mead, Simon; Lashley, Tammaryn; Wray, Selina; Sidle, Katie; Fratta, Pietro; Orrell, Richard W.; Hardy, John; Holton, Janice L.; Révész, Tamás; Rossor, Martin N.; Warren, Jason D.

doi:10.1016/s1474-4422(14)70233-9

Cited by 205 publications

(197 citation statements)

References 139 publications

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“…ALS-linked mutations in the RNAbinding proteins fused in sarcoma and TDP-43 were discovered, and the repeat expansions in C9orf72, whose mechanism is yet unknown, was also suggested to contribute to ALS-associated neurodegeneration through RNA toxicity (46). ANAT predictions pointed to Staufen1 as a central node in both the mutant SOD1 and wild-type networks.…”

Section: Als-linked Mutations Affect the Synaptic Localization Of Stamentioning

confidence: 99%

Proteomic Analysis of Dynein-Interacting Proteins in Amyotrophic Lateral Sclerosis Synaptosomes Reveals Alterations in the RNA-Binding Protein Staufen1

Gershoni-Emek

Mazza

Chein

et al. 2016

Molecular & Cellular Proteomics

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Synapse disruption takes place in many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the mechanistic understanding of this process is still limited. We set out to study a possible role for dynein in synapse integrity. Cytoplasmic dynein is a multisubunit intracellular molecule responsible for diverse cellular functions, including long-distance transport of vesicles, organelles, and signaling factors toward the cell center. A less well-characterized role dynein may play is the spatial clustering and anchoring of various factors including mRNAs in distinct cellular domains such as the neuronal synapse. Here, in order to gain insight into dynein functions in synapse integrity and disruption, we performed a screen for novel dynein interactors at the synapse. Dynein immunoprecipitation from synaptic fractions of the ALS model mSOD1 G93A and wild-type controls, followed by mass spectrometry analysis on synaptic fractions of the ALS model mSOD1 G93A and wild-type controls, was performed. Using advanced network analysis, we identified Staufen1, an RNA-binding protein required for the transport and localization of neuronal RNAs, as a major mediator of dynein interactions via its interaction with protein phosphatase 1-beta (PP1B). Both in vitro and in vivo validation assays demonstrate the interactions of Staufen1 and PP1B with dynein, and their colocalization with synaptic markers was altered as a result of two separate ALS-linked mutations: mSOD1 G93A and TDP43 A315T. Taken together, we suggest a model in which dynein's interaction with Staufen1 regulates mRNA localization along the axon and the synapses, and alterations in this process may correlate with synapse disruption and ALS toxicity. Molecular & Cellular

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Section: Als-linked Mutations Affect the Synaptic Localization Of Stamentioning

confidence: 99%

Proteomic Analysis of Dynein-Interacting Proteins in Amyotrophic Lateral Sclerosis Synaptosomes Reveals Alterations in the RNA-Binding Protein Staufen1

Gershoni-Emek

Mazza

Chein

et al. 2016

Molecular & Cellular Proteomics

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“…The characteristic pathological findings in both ALS and FTD are of dipeptide repeat (DPR) proteins. Possible molecular mechanisms of neurodegeneration include loss or gain of the C9orf72 protein function (10,17). Loss of protein function reflects reduced levels of C9orf72 in patients' brain and functional work revealing a role of C9orf72 protein in endocyclic and autophagic pathways (17).…”

Section: Geneticsmentioning

confidence: 99%

“…The presence of frontotemporal impairment in ALS predicts a shorter survival time (8) and behavioural and functional impairment may decline independently of motor function (9,10).…”

mentioning

confidence: 99%

Molecular basis of ALS and FTD: implications for translational studies / Molekularna osnova ALS-a i FTD-a: implikacije za translacijska istraživanja

Liščić

2015

Archives of Industrial Hygiene and Toxicology

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders, related by signs of deteriorating motor and cognitive functions, and short survival. The cause is unknown and no effective treatment currently exists. For ALS, there is only a drug Riluzole and a promising substance arimoclomol. The overlap between ALS and FTD occurs at clinical, genetic, and pathological levels. The majority of ALS cases are sporadic (SALS) and a subset of patients has an inherited form of the disease, familial ALS (FALS), with a common SOD1 mutation, also present in SALS. A few of the mutant genes identified in FALS have also been found in SALS. Recently, hexanucleotide repeat expansions in C9ORF72 gene were found to comprise the largest fraction of ALS-and FTD-causing mutations known to date. TAR DNA-binding protein 43 , encoded by the TARDBP gene, has been identified as the pathological protein of FALS, SALS and, less frequently, FTD. The less frequent TDP-43 pathology in other forms of familial FTD has been linked to a range of mutations in GRN, FUS/TLS, rarely VCP, and other genes. TDP-43 and FUS/TLS have striking structural and functional similarities, most likely implicating altered RNA processing as a major event in ALS pathogenesis. The clinical overlap of the symptoms of FTD and ALS is complemented by overlapping neuropathology, with intracellular inclusions composed of microtubule-associated protein tau, TDP-43 and less frequently FUS, or unknown ubiquitinated proteins. Furthermore, new therapeutic approaches continue to emerge, by targeting SOD1, TDP-43 or GRN proteins. This review addresses new advances that are being made in our understanding of the molecular mechanisms of both diseases, which may eventually translate into new treatment options. KEY WORDS: dementia; FTLD; FUS/TLS; genetics; motor neuron disease; TDP-43; C9ORF72 nucleotide repeat expansions; TARDBP Liščić RM, Molecular basis of ALS and FTD: Implications for translational studies Arh Hig Rada Toksikol 2015;66:285-290 Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative disorders, which are characterised by decline in motor and cognitive functions, and short survival. ALS is clinically characterised by signs of upper and lower motor neuron degeneration and its progressive spread of signs within a region or to other regions in a time frame, as defined by the revised El Escorial criteria (1). Both diseases have fatal outcome within a few years' time (1). The cause is unknown and no effective treatment currently exists. There is a drug Riluzole, which slightly prolongs survival in patients with ALS (2), and a Phase II/III randomised, placebo-controlled trials of arimoclomol (BRX-345) in familial ALS with SOD-1 mutation (NCT00706147; www.clinicaltrials.gov). The substance arimoclomol may reduce the levels of protein aggregates in motor nerves, a possible cause of ALS, by boosting expression of chaperons Hsp 70 and Hsp 90 which help newly synthesised proteins properly fol...

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“…The most studied of these fALS genes is SOD1 (superoxide dismutase-1, aka CuZn SOD, aka cytosolic SOD), with over 100 causal mutations known. The most frequently occurring mutated fALS gene is a hexanucleotide repeat in the promoter or first exon of orf72, located on Chromosome 9, thus C9orf72 [1,[3][4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Laser-captured spinal cord motorneurons from ALS subjects show increased gene expression in vacuolar ATPase networks

Ladd¹,

Brohawn²,

Bennett³

2017

J Syst Integr Neurosci

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Amyotrophic lateral sclerosis (ALS), a systems neurodegeneration of adults, is typically progressive, fatal, and arises from death of lower and upper motorneurons (MN's). We carried out RNA sequencing (RNA-seq) from cervical spinal cord MN's isolated with laser capture microdissection (LCM) from ALS (n=4) and CTL (n=6) subjects. Cufflinks estimation of FPKM values (fragments per kilobase of exon per million reads), identified 3868 genes where the minimal mean FPKM was 2.0 in both groups. "Biologically blind" plots showed gene expression in ALS MN's was increased 2 to 7-fold compared to CTL MN gene expression.

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C9orf72 expansions in frontotemporal dementia and amyotrophic lateral sclerosis

Cited by 205 publications

References 139 publications

Proteomic Analysis of Dynein-Interacting Proteins in Amyotrophic Lateral Sclerosis Synaptosomes Reveals Alterations in the RNA-Binding Protein Staufen1

Proteomic Analysis of Dynein-Interacting Proteins in Amyotrophic Lateral Sclerosis Synaptosomes Reveals Alterations in the RNA-Binding Protein Staufen1

Molecular basis of ALS and FTD: implications for translational studies / Molekularna osnova ALS-a i FTD-a: implikacije za translacijska istraživanja

Laser-captured spinal cord motorneurons from ALS subjects show increased gene expression in vacuolar ATPase networks

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