NEK1 loss-of-function mutation induces DNA damage accumulation in ALS patient-derived motoneurons

Publication date: Available online 12 June 2018 Source:Stem Cell Research Author(s): Julia Higelin, Alberto Catanese, Lena Luisa Semelink-Sedlacek, Sertap Oeztuerk, Anne-Kathrin Lutz, Julia Bausinger, Gotthold Barbi, Günter Speit, Peter M. Andersen, Albert C. Ludolph, Maria Demestre, Tobias M. Boeckers Mutations in genes coding for proteins involved in DNA damage response (DDR) and repair, such as C9orf72 and FUS (Fused in Sarcoma), are associated with neurodegenerative diseases and lead to amyotrophic lateral sclerosis (ALS). Heterozygous loss-of-function mutations in NEK1 (NIMA-related kinase 1) have also been recently found to cause ALS. NEK1 codes for a multifunctional protein, crucially involved in mitotic checkpoint control and DDR. To resolve pathological alterations associated with NEK1 mutation, we compared hiPSC-derived motoneurons carrying a NEK1 mutation with mutant C9orf72 and wild type neurons at basal level and after DNA damage induction. Motoneurons carrying a C9orf72 mutation exhibited cell specific signs of increased DNA damage. This phenotype was even more severe in NEK1c.2434A>T neurons that showed significantly increased DNA damage at basal level and impaired DDR after induction of DNA damage in an maturation-dependent manner. Our results provide first mechanistic insight in pathophysiological alterations induced by NEK1 mutations and point to a converging pathomechanism of different gene mutations causative for ALS. Therefore, our study contribu...
Source: Stem Cell Research - Category: Stem Cells Source Type: research

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We describe a 19-year-old woman who was admitted to our hospital because of rapidly progressive dysarthria and dysphagia, developing over the course of 3  months. She had no family history of neurological diseases including essential tremor and no consanguineous history. Her delivery was non-eventful. In elementary school, her school records were not so bad, but she was not able to get along with her classmates.
Source: Journal of the Neurological Sciences - Category: Neurology Authors: Tags: Letter to the Editor Source Type: research
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by preferential motor neuron death. Approximately 15% of ALS cases are familial, and mutations in the fused in sarcoma (FUS) gene contribute to a subset of familial ALS cases. FUS is a multifunctional protein participating in many RNA metabolism pathways....
Source: Proceedings of the National Academy of Sciences - Category: Science Authors: Tags: PNAS Plus Source Type: research
CONCLUSIONS We identified a novel frameshift mutation associated with JALS. JALS and generally typical ALS, with the same FUS mutation, can appear in a family and present a phenomenon of anticipation. For diagnosis of central nervous system degeneration in adolescents with bulbar symptoms, great attention should be paid to JALS. PMID: 30507891 [PubMed - in process]
Source: Medical Science Monitor - Category: Research Tags: Med Sci Monit Source Type: research
Publication date: Available online 24 November 2018Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseAuthor(s): Junghee Lee, Phuong T. Nguyen, Hyun-Soo Shim, Seung Jae Hyeon, Hyeonjoo Im, Mi-Hyun Choi, Sooyoung Chung, Neil W. Kowall, Sean Bong Lee, Hoon RyuAbstractEwing's sarcoma (EWS) is a bone cancer arising predominantly in young children. EWSR1 (Ewing Sarcoma breakpoint region 1/EWS RNA binding protein 1) gene is ubiquitously expressed in most cell types, indicating it has diverse roles in various cellular processes and organ development. Recently, several studies have shown that missense mutation...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research
FUS (fused in sarcoma) proteinopathy is a group of neurodegenerative diseases characterized by the formation of inclusion bodies containing the FUS protein, including frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Previous studies show that mitochondrial damage is an important aspect of FUS proteinopathy. However, the molecular mechanisms by which FUS...
Source: Proceedings of the National Academy of Sciences - Category: Science Authors: Tags: PNAS Plus Source Type: research
Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder. There are several genetic mutations that lead to ALS development, such as chromosome 9 hexanucleotide repeat 72 (C9ORF72), transactive response DNA-binding protein (TARDBP), superoxide dismutase 1 (SOD1) and fused in sarcoma (FUS). ALS is associated with disrupted gene homeostasis causing aberrant RNA processing or toxic pathology. Several animal models of ALS disease have been developed to understand whether TARDBP-mediated neurodegeneration results from a gain or a loss of function of the protein, however, none exactly mimic the pathop...
Source: In Vivo - Category: Research Authors: Tags: Reviews Source Type: research
Publication date: 24 July 2018Source: Cell Reports, Volume 24, Issue 4Author(s): Eva-Maria Hock, Zuzanna Maniecka, Marian Hruska-Plochan, Stefan Reber, Florent Laferrière, Sonu Sahadevan M.K., Helena Ederle, Lauren Gittings, Lucas Pelkmans, Luc Dupuis, Tammaryn Lashley, Marc-David Ruepp, Dorothee Dormann, Magdalini PolymenidouSummaryThe primarily nuclear RNA-binding protein FUS (fused in sarcoma) forms pathological cytoplasmic inclusions in a subset of early-onset amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. In response to cellular stress, FUS is recruited to cytoplasmic stress gra...
Source: Cell Reports - Category: Cytology Source Type: research
Publication date: July 2018Source: Stem Cell Research, Volume 30Author(s): Julia Higelin, Alberto Catanese, Lena Luisa Semelink-Sedlacek, Sertap Oeztuerk, Anne-Kathrin Lutz, Julia Bausinger, Gotthold Barbi, Günter Speit, Peter M. Andersen, Albert C. Ludolph, Maria Demestre, Tobias M. BoeckersAbstractMutations in genes coding for proteins involved in DNA damage response (DDR) and repair, such as C9orf72 and FUS (Fused in Sarcoma), are associated with neurodegenerative diseases and lead to amyotrophic lateral sclerosis (ALS). Heterozygous loss-of-function mutations in NEK1 (NIMA-related kinase 1) have also been recently...
Source: Stem Cell Research - Category: Stem Cells Source Type: research
Authors: Azuma Y, Mizuta I, Tokuda T, Mizuno T Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects upper and lower motor neurons in the brain and the spinal cord. Due to the progressive neurodegeneration, ALS leads to paralysis and death caused by respiratory failure 2-5 years after the onset of symptoms. There is no effective cure available. Most ALS cases are sporadic, without family history, whereas 10% of the cases are familial. Identification of variants in more than 30 different loci has provided insight into the pathogenic molecular mechanisms mediating disease...
Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
Publication date: 2018 Source:Handbook of Clinical Neurology, Volume 153 Author(s): Jacob I. Ayers, Neil R. Cashman The prion hypothesis – a protein conformation capable of replicating without a nucleic acid genome – was heretical at the time of its discovery. However, the characteristics of the disease-misfolded prion protein and its ability to transmit disease, replicate, and spread are now widely accepted throughout the scientific community. In fact, in the last decade a wealth of evidence has emerged supporting similar properties observed for many of the misfolded proteins implicated in other neurodegenera...
Source: Handbook of Clinical Neurology - Category: Neurology Source Type: research
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