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Bita Zamiri, Mila Mirceta, Rashid Abu-Ghazalah, Marc S Wold, Christopher E Pearson, Robert B Macgregor
BACKGROUND: Expansion of the C9orf72 hexanucleotide repeat (GGGGCC)n •(GGCCCC)n is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both strands of the C9orf72 repeat have been shown to form unusual DNA and RNA structures that are thought to be involved in mutagenesis and/or pathogenesis. We previously showed that the C-rich DNA strands from the C9orf72 repeat can form four-stranded quadruplexes at neutral pH. The cytosine residues become protonated under slightly acidic pH (pH 4...
March 14, 2018: Biochimica et Biophysica Acta
Noori Chai, Aaron D Gitler
A hexanucleotide repeat expansion in the C9orf72 gene has been identified as the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. The expanded hexanucleotide repeat is translated by an unconventional mechanism to produce five species of dipeptide repeat proteins (DPRs), glycine-proline (GP), glycine-alanine, glycine-arginine (GR), proline-alanine (PA), and proline-arginine (PR). Of these, the arginine-rich ones, PR and GR, are highly toxic in a variety of model systems, ranging from human cells, to Drosophila, to even the budding yeast, Saccharomyces cerevisiae...
March 8, 2018: FEMS Yeast Research
Amrutha Swaminathan, Marilou Bouffard, Meijiang Liao, Sarah Ryan, Janis Bennion Callister, Stuart M Pickering-Brown, Gary Alan Barclay Armstrong, Pierre Drapeau
Large expansions of hexanucleotide GGGGCC (G4C2) repeats (hundreds to thousands) in the first intron of the chromosome 9 open reading frame 72 (C9orf72) locus are the strongest known genetic factor associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS/FTLD). Different hypotheses exist about the underlying disease mechanism including loss-of-function by haploinsufficiency, toxicity arising as a result of RNA or dipeptide repeats (DPRs). Five different DPRs are produced by repeat-associated non-ATG-initiated (RAN) translation of the G4C2 repeats...
March 8, 2018: Human Molecular Genetics
Anna Bartoletti-Stella, Simone Baiardi, Michelangelo Stanzani-Maserati, Silvia Piras, Paolo Caffarra, Alberto Raggi, Roberta Pantieri, Sara Baldassari, Leonardo Caporali, Samir Abu-Rumeileh, Simona Linarello, Rocco Liguori, Piero Parchi, Sabina Capellari
Genetics is intricately involved in the etiology of neurodegenerative dementias. The incidence of monogenic dementia among all neurodegenerative forms is unknown due to the lack of systematic studies and of patient/clinician access to extensive diagnostic procedures. In this study, we conducted targeted sequencing in 246 clinically heterogeneous patients, mainly with early-onset and/or familial neurodegenerative dementia, using a custom-designed next-generation sequencing panel covering 27 genes known to harbor mutations that can cause different types of dementia, in addition to the detection of C9orf72 repeat expansions...
February 13, 2018: Neurobiology of Aging
Merit Lamp, Paola Origone, Alessandro Geroldi, Simonetta Verdiani, Fabio Gotta, Claudia Caponnetto, Grazia Devigili, Lorenzo Verriello, Carlo Scialò, Corrado Cabona, Antonio Canosa, Irene Vanni, Emilia Bellone, Roberto Eleopra, Paola Mandich
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a heterogeneous genetic background. Because mutation analysis by Sanger sequencing is costly and time-consuming, in recent years, next-generation sequencing (NGS) techniques have become of much interest. This study analyses the results of 20 years of molecular analyses in ALS patients in our laboratory using traditional methods and NGS. Almost 300 ALS patients underwent genetic analysis with Sanger sequencing of 7 genes or with an NGS panel of 23 genes...
February 1, 2018: Neurobiology of Aging
Tu-Hsueh Yeh, Han-Fang Liu, Yu-Wen Li, Chin-Song Lu, Hung-Yu Shih, Ching-Chi Chiu, Sheng-Jia Lin, Yin-Cheng Huang, Yi-Chuan Cheng
Hexanucleotide repeat expansions in the C9orf72 gene are a common genetic cause of familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the function of C9orf72 in neural development and the pathogenic mechanism underlying neurodegeneration are unknown. We found that disrupting C9orf72 expression by using C9orf72 constructs that lack the complete DENN domain result in reduced GTPase activity in zebrafish embryos, demonstrating the indispensability of the complete DENN domain...
March 6, 2018: Experimental Neurology
Emily R Seminary, Samantha L Sison, Allison D Ebert
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder caused by the selective loss of the upper and lower motor neurons. Only 10% of all cases are caused by a mutation in one of the two dozen different identified genes, while the remaining 90% are likely caused by a combination of as yet unidentified genetic and environmental factors. Mutations in C9orf72, SOD1 , or TDP-43 are the most common causes of familial ALS, together responsible for at least 60% of these cases. Remarkably, despite the large degree of heterogeneity, all cases of ALS have protein aggregates in the brain and spinal cord that are immunopositive for SOD1, TDP-43, OPTN, and/or p62...
2018: Frontiers in Neuroscience
Kathryn Volkening, Brian Keller, Cheryl Leysta-Lantz, Michael J Strong
Tar DNA binding protein of 43kDa (TDP-43) is a dual function RNA/DNA binding protein with varied cellular functions. In degenerating motor neurons in ALS, TDP-43 relocalizes from the nucleus to the cytosol where it is sequestered into inclusions. It is likely that the pathogenic role of TDP-43 in ALS can involve either a gain or a loss of function, depending on the nature of its RNA or protein interactor. However, while TDP-43 binding partners have been identified in a range of model systems and from the human brain, interactors from human spinal cord tissue have not...
March 7, 2018: Journal of Proteome Research
Nicholas J Kramer, Michael S Haney, David W Morgens, Ana Jovičić, Julien Couthouis, Amy Li, James Ousey, Rosanna Ma, Gregor Bieri, C Kimberly Tsui, Yingxiao Shi, Nicholas T Hertz, Marc Tessier-Lavigne, Justin K Ichida, Michael C Bassik, Aaron D Gitler
Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons...
March 5, 2018: Nature Genetics
Xiaolu Liu, Ji He, Fen-Biao Gao, Aaron D Gitler, Dongsheng Fan
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with loss of motor neurons. Previous knowledge of the disease has been mainly based on studies from Caucasian ALS patients of European descent. Here we review the epidemiological characteristics of ALS among the Chinese population in order to compare the similarities and differences between Chinese ALS cases and those from other countries. We describe a potential lower incidence and prevalence of ALS, a younger age of onset and a lower proportion of familial ALS cases in the Chinese population...
March 1, 2018: Brain Research
Philippe Corcia, Patrick Vourc'h, Helene Blasco, Philippe Couratier, Audrey Dangoumau, Remi Bellance, Claude Desnuelle, Fausto Viader, Vivien Pautot, Stephanie Millecamps, Salah Bakkouche, FranÇois Salachas, Christian R Andres, Vincent Meininger, William Camu
BACKGROUND: Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most frequent motor neuron disorders in adulthood and infancy, respectively. There is a growing literature supporting common pathophysiological patterns between those disorders. One important clinical issue for that is the co-occurrence of both diseases within a family. OBJECTIVES: To collect families in which ALS and SMA patients co-exist and describe the phenotype and the genotype of ALS patients...
March 1, 2018: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Dawn H W Lau, Naomi Hartopp, Natalie J Welsh, Sarah Mueller, Elizabeth B Glennon, Gábor M Mórotz, Ambra Annibali, Patricia Gomez-Suaga, Radu Stoica, Sebastien Paillusson, Christopher C J Miller
Fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two related and incurable neurodegenerative diseases. Features of these diseases include pathological protein inclusions in affected neurons with TAR DNA-binding protein 43 (TDP-43), dipeptide repeat proteins derived from the C9ORF72 gene, and fused in sarcoma (FUS) representing major constituent proteins in these inclusions. Mutations in C9ORF72 and the genes encoding TDP-43 and FUS cause familial forms of FTD/ALS which provides evidence to link the pathology and genetics of these diseases...
February 28, 2018: Cell Death & Disease
Lucia Corrado, Cinzia Tiloca, Clarissa Locci, Alessandra Bagarotti, Hamid Hamzeiy, Claudia Colombrita, Fabiola De Marchi, Nadia Barizzone, Diego Cotella, Nicola Ticozzi, Letizia Mazzini, Ayse Nazli Basak, Antonia Ratti, Vincenzo Silani, Sandra D'alfonso
Large expansions of a noncoding GGGGCC repeat in the C9orf72 gene are the main cause of amyotrophic lateral sclerosis (ALS). The GGGGCC repeat is contiguous with another GC-rich region. Recent studies reported a significantly higher frequency of insertions/deletions within the GC-rich region in patients carrying the GGGGCC expansion. A GTGGT motif comprised within the GC-rich region, which joins two 100% GC sequences, was frequently deleted, supporting the hypothesis that these deletions could make the region more prone to slippage and pathological expansion...
February 28, 2018: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Maria Pia Giannoccaro, Anna Bartoletti-Stella, Silvia Piras, Alfonsina Casalena, Federico Oppi, Giovanni Ambrosetto, Pasquale Montagna, Rocco Liguori, Piero Parchi, Sabina Capellari
BACKGROUND: In 1969, Dazzi and Finizio reported the second observation of frontotemporal dementia (FTD) - amyotrophic lateral sclerosis (ALS) association in a large Italian kindred affected by an autosomal dominant form of ALS with high penetrance, frequent bulbar onset, and frequent cognitive decline. OBJECTIVE: To expand the original characterization of this family and report the link with the C9orf72 repeat expansion (RE). METHODS: We followed or reviewed the medical records of thirteen patients belonging to the original family and performed genetic analyses in four individuals...
2018: Journal of Alzheimer's Disease: JAD
Kasper Katisko, Annakaisa Haapasalo, Anne Koivisto, Johanna Krüger, Päivi Hartikainen, Ville Korhonen, Seppo Helisalmi, Sanna-Kaisa Herukka, Anne M Remes, Eino Solje
 Several studies have reported reduced risk of cancer in patients with Alzheimer's disease (AD) or Parkinson's disease. The relationship between cancer and frontotemporal lobar degeneration (FTLD) has not been previously reported. Here, our aim was to evaluate the occurrence of cancer in Finnish FTLD patients with a high proportion of C9ORF72 repeat expansion carriers in comparison to age- and sex-matched group of AD patients and control subjects classified as not cognitively impaired (NCI). The prevalence of cancer was 9...
2018: Journal of Alzheimer's Disease: JAD
Shalini Iyer, K Ravi Acharya, Vasanta Subramanian
C9orf72 is associated with frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS), both of which are devastating neurodegenerative diseases. Findings suggest that an expanded hexanucleotide repeat in the non-coding region of the C9orf72 gene is the most common cause of familial FTD and ALS. Despite considerable efforts being made towards discerning the possible disease-causing mechanism/s of this repeat expansion mutation, the biological function of C9orf72 remains unclear. Here, we present the first comprehensive genomic study on C9orf72 gene...
2018: PeerJ
Stephen A Goutman, Kevin S Chen, Ximena Paez-Colasante, Eva L Feldman
Amyotrophic lateral sclerosis (ALS) is a progressive, noncurable neurodegenerative disorder of the upper and lower motor neurons causing weakness and death within a few years of symptom onset. About 10% of patients with ALS have a family history of the disease; however, ALS-associated genetic mutations are also found in sporadic cases. There are over 100 ALS-associated mutations, and importantly, several genetic mutations, including C9ORF72, SOD1, and TARDBP, have led to mechanistic insight into this complex disease...
2018: Handbook of Clinical Neurology
Petra Pasanen, Liisa Myllykangas, Minna Pöyhönen, Anna Kiviharju, Maija Siitonen, John Hardy, Jose Bras, Anders Paetau, Pentti J Tienari, Rita Guerreiro, Auli Verkkoniemi-Ahola
Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two most common neurodegenerative dementias. Variants in APP, PSEN1 and PSEN2 are typically linked to early-onset AD, and several genetic risk loci are associated with late-onset AD. Inherited FTD can be caused by hexanucleotide expansions in C9orf72, or variants in GRN, MAPT or CHMP2B. Several other genes have also been linked to FTD or FTD with motor neuron disease. Here we describe a cohort of 60 Finnish families with possible inherited dementia...
February 23, 2018: European Journal of Human Genetics: EJHG
Charlotte Ridler
No abstract text is available yet for this article.
February 23, 2018: Nature Reviews. Neurology
Hongbo Chen, Mark W Kankel, Susan C Su, Steve W S Han, Dimitry Ofengeim
Although amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, was first described in 1874, a flurry of genetic discoveries in the last 10 years has markedly increased our understanding of this disease. These findings have not only enhanced our knowledge of mechanisms leading to ALS, but also have revealed that ALS shares many genetic causes with another neurodegenerative disease, frontotemporal lobar dementia (FTLD). In this review, we survey how recent genetic studies have bridged our mechanistic understanding of these two related diseases and how the genetics behind ALS and FTLD point to complex disorders, implicating non-neuronal cell types in disease pathophysiology...
February 19, 2018: Cell Death and Differentiation
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