Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons. Although novel ALS genetic variants have been identified, the shared genetic risk between ALS and other neurodegenerative disorders remains poorly understood.

Related collections

Most cited references 13

Record: found
Abstract: found
Article: found

Is Open Access

Genome-wide identification of splicing QTLs in the human brain and their enrichment among schizophrenia-associated loci

Atsushi Takata, Naomichi Matsumoto, Tadafumi Kato (2017)

Detailed analyses of transcriptome have revealed complexity in regulation of alternative splicing (AS). These AS events often undergo modulation by genetic variants. Here we analyse RNA-sequencing data of prefrontal cortex from 206 individuals in combination with their genotypes and identify cis-acting splicing quantitative trait loci (sQTLs) throughout the genome. These sQTLs are enriched among exonic and H3K4me3-marked regions. Moreover, we observe significant enrichment of sQTLs among disease-associated loci identified by GWAS, especially in schizophrenia risk loci. Closer examination of each schizophrenia-associated loci revealed four regions (each encompasses NEK4, FXR1, SNAP91 or APOPT1), where the index SNP in GWAS is in strong linkage disequilibrium with sQTL SNP(s), suggesting dysregulation of AS as the underlying mechanism of the association signal. Our study provides an informative resource of sQTL SNPs in the human brain, which can facilitate understanding of the genetic architecture of complex brain disorders such as schizophrenia.

0 comments Cited 91 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Is Open Access

The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease

Lauren D Stutzbach, Sharon Xie, Adam Naj … (2013)

Background Progressive supranuclear palsy (PSP) is a neurodegenerative disorder pathologically characterized by intracellular tangles of hyperphosphorylated tau protein distributed throughout the neocortex, basal ganglia, and brainstem. A genome-wide association study identified EIF2AK3 as a risk factor for PSP. EIF2AK3 encodes PERK, part of the endoplasmic reticulum’s (ER) unfolded protein response (UPR). PERK is an ER membrane protein that senses unfolded protein accumulation within the ER lumen. Recently, several groups noted UPR activation in Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, multiple system atrophy, and in the hippocampus and substantia nigra of PSP subjects. Here, we evaluate UPR PERK activation in the pons, medulla, midbrain, hippocampus, frontal cortex and cerebellum in subjects with PSP, AD, and in normal controls. Results We found UPR activation primarily in disease-affected brain regions in both disorders. In PSP, the UPR was primarily activated in the pons and medulla and to a much lesser extent in the hippocampus. In AD, the UPR was extensively activated in the hippocampus. We also observed UPR activation in the hippocampus of some elderly normal controls, severity of which positively correlated with both age and tau pathology but not with Aβ plaque burden. Finally, we evaluated EIF2AK3 coding variants that influence PERK activation. We show that a haplotype associated with increased PERK activation is genetically associated with increased PSP risk. Conclusions The UPR is activated in disease affected regions in PSP and the genetic evidence shows that this activation increases risk for PSP and is not a protective response.

0 comments Cited 81 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Role of mutant SOD1 disulfide oxidation and aggregation in the pathogenesis of familial ALS.

D Winkler, David Borchelt, Celeste Karch … (2009)

Transgenic mice that model familial (f)ALS, caused by mutations in superoxide dismutase (SOD)1, develop paralysis with pathology that includes the accumulation of aggregated forms of the mutant protein. Using a highly sensitive detergent extraction assay, we traced the appearance and abundance of detergent-insoluble and disulfide cross-linked aggregates of SOD1 throughout the disease course of SOD1-fALS mice (G93A, G37R, and H46R/H48Q). We demonstrate that the accumulation of disulfide cross-linked, detergent-insoluble, aggregates of mutant SOD1 occurs primarily in the later stages of the disease, concurrent with the appearance of rapidly progressing symptoms. We find no evidence for a model in which aberrant intermolecular disulfide bonding has an important role in promoting the aggregation of mutant SOD1, instead, such cross-linking appears to be a secondary event. Also, using both cell culture and mouse models, we find that mutant protein lacking the normal intramolecular disulfide bond is a major component of the insoluble SOD1 aggregates. Overall, our findings suggest a model in which soluble forms of mutant SOD1 initiate disease with larger aggregates implicated only in rapidly progressing events in the final stages of disease. Within the final stages of disease, abnormalities in the oxidation of a normal intramolecular disulfide bond in mutant SOD1 facilitate the aggregation of mutant protein.

0 comments Cited 64 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Title: JAMA Neurology

Abbreviated Title: JAMA Neurol

Publisher: American Medical Association (AMA)

ISSN (Print): 2168-6149

Publication date Created: July 01 2018

Publication date (Print): July 01 2018

Volume: 75

Issue: 7

Page: 860

Affiliations

[1 ]Department of Psychiatry, Washington University in St Louis, St Louis, Missouri

[2 ]Department of Cognitive Sciences, University of California, San Diego, La Jolla

[3 ]Memory and Aging Center, Department of Neurology, University of California, San Francisco

[4 ]Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida

[5 ]Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases, Munich, Germany

[6 ]Department of Neurology, Technical University of Munich, Munich Cluster for Systems Neurology SyNergy, Munich, Germany

[7 ]Institut for Humangenetik, Justus-Liebig-Universität, Giessen, Germany

[8 ]Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom

[9 ]Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia

[10 ]Center for Applied Genomics, Abramson Research Center, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

[11 ]Division of Human Genetics, Abramson Research Center, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

[12 ]Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia

[13 ]Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock

[14 ]Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco

[15 ]Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany

[16 ]Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany

[17 ]Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway

[18 ]Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway

[19 ]Department of Neurosciences, University of California, San Diego, La Jolla

[20 ]Department of Neurosciences and Radiology, University of California, San Diego, La Jolla

Article

DOI: 10.1001/jamaneurol.2018.0372

PMC ID: 6043387

PubMed ID: 29630712

SO-VID: 0b68fcb1-2081-45fb-a38e-18db44b49007

History

Data availability:

Comments

Comment on this article

scite_

Cited by 40

See all cited by

Most referenced authors 2,360

See all reference authors

- Version 1
- Version 1

Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum

Read this article at

Abstract

Related collections

UCL: UN SDG 03 Good Health and Well-Being

Most cited references 13

Genome-wide identification of splicing QTLs in the human brain and their enrichment among schizophrenia-associated loci

The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease

Role of mutant SOD1 disulfide oxidation and aggregation in the pathogenesis of familial ALS.

Author and article information

Journal

Affiliations

Article

History

Comments

Comment on this article

Similar content 2,464

Cited by 40

Most referenced authors 2,360