TDP43 proteinopathy is associated with aberrant DNA methylation in human amyotrophic lateral sclerosis

Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neurone (MN) degeneration and death. ALS can be sporadic (sALS) or familial, with a number of associated gene mutations, including C9orf72 (C9ALS). DNA methylation is an epigenetic mechanism wh...

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Veröffentlicht in:Neuropathology and applied neurobiology 2021-02, Vol.47 (1), p.61-72
Hauptverfasser: Appleby‐Mallinder, C., Schaber, E., Kirby, J., Shaw, P. J., Cooper‐Knock, J., Heath, P. R., Highley, J. R.
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container_end_page 72
container_issue 1
container_start_page 61
container_title Neuropathology and applied neurobiology
container_volume 47
creator Appleby‐Mallinder, C.
Schaber, E.
Kirby, J.
Shaw, P. J.
Cooper‐Knock, J.
Heath, P. R.
Highley, J. R.
description Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neurone (MN) degeneration and death. ALS can be sporadic (sALS) or familial, with a number of associated gene mutations, including C9orf72 (C9ALS). DNA methylation is an epigenetic mechanism whereby a methyl group is attached to a cytosine (5mC), resulting in gene expression repression. 5mC can be further oxidized to 5‐hydroxymethylcytosine (5hmC). DNA methylation has been studied in other neurodegenerative diseases, but little work has been conducted in ALS. Aims To assess differences in DNA methylation in individuals with ALS and the relationship between DNA methylation and TDP43 pathology. Methods Post mortem tissue from controls, sALS cases and C9ALS cases were assessed by immunohistochemistry for 5mC and 5hmC in spinal cord, motor cortex and prefrontal cortex. LMNs were extracted from a subset of cases using laser capture microdissection. DNA from these underwent analysis using the MethylationEPIC array to determine which molecular processes were most affected. Results There were higher levels of 5mC and 5hmC in sALS and C9ALS in the residual lower motor neurones (LMNs) of the spinal cord. Importantly, in LMNs with TDP43 pathology there was less nuclear 5mC and 5hmC compared to the majority of residual LMNs that lacked TDP43 pathology. Enrichment analysis of the array data suggested RNA metabolism was particularly affected. Conclusions DNA methylation is a contributory factor in ALS LMN pathology. This is not so for glia or neocortical neurones.
doi_str_mv 10.1111/nan.12625
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J. ; Cooper‐Knock, J. ; Heath, P. R. ; Highley, J. R.</creator><creatorcontrib>Appleby‐Mallinder, C. ; Schaber, E. ; Kirby, J. ; Shaw, P. J. ; Cooper‐Knock, J. ; Heath, P. R. ; Highley, J. R.</creatorcontrib><description>Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neurone (MN) degeneration and death. ALS can be sporadic (sALS) or familial, with a number of associated gene mutations, including C9orf72 (C9ALS). DNA methylation is an epigenetic mechanism whereby a methyl group is attached to a cytosine (5mC), resulting in gene expression repression. 5mC can be further oxidized to 5‐hydroxymethylcytosine (5hmC). DNA methylation has been studied in other neurodegenerative diseases, but little work has been conducted in ALS. Aims To assess differences in DNA methylation in individuals with ALS and the relationship between DNA methylation and TDP43 pathology. Methods Post mortem tissue from controls, sALS cases and C9ALS cases were assessed by immunohistochemistry for 5mC and 5hmC in spinal cord, motor cortex and prefrontal cortex. LMNs were extracted from a subset of cases using laser capture microdissection. DNA from these underwent analysis using the MethylationEPIC array to determine which molecular processes were most affected. Results There were higher levels of 5mC and 5hmC in sALS and C9ALS in the residual lower motor neurones (LMNs) of the spinal cord. Importantly, in LMNs with TDP43 pathology there was less nuclear 5mC and 5hmC compared to the majority of residual LMNs that lacked TDP43 pathology. Enrichment analysis of the array data suggested RNA metabolism was particularly affected. Conclusions DNA methylation is a contributory factor in ALS LMN pathology. This is not so for glia or neocortical neurones.</description><identifier>ISSN: 0305-1846</identifier><identifier>EISSN: 1365-2990</identifier><identifier>DOI: 10.1111/nan.12625</identifier><identifier>PMID: 32365404</identifier><language>eng</language><publisher>England: Wiley Subscription Services, Inc</publisher><subject>Amyotrophic lateral sclerosis ; Cortex (motor) ; Cytosine ; Deoxyribonucleic acid ; DNA ; DNA hydroxymethylation ; DNA methylation ; Epigenetics ; Gene expression ; Immunohistochemistry ; Motor neurone disease ; Neurodegeneration ; Neurodegenerative diseases ; Neuronal-glial interactions ; Pathology ; Prefrontal cortex ; Ribonucleic acid ; RNA ; Spinal cord</subject><ispartof>Neuropathology and applied neurobiology, 2021-02, Vol.47 (1), p.61-72</ispartof><rights>2020 The Authors. published by John Wiley &amp; Sons Ltd on behalf of British Neuropathological Society</rights><rights>2020 The Authors. Neuropathology and Applied Neurobiology published by John Wiley &amp; Sons Ltd on behalf of British Neuropathological Society.</rights><rights>2020. This article is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). 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J.</creatorcontrib><creatorcontrib>Cooper‐Knock, J.</creatorcontrib><creatorcontrib>Heath, P. R.</creatorcontrib><creatorcontrib>Highley, J. R.</creatorcontrib><title>TDP43 proteinopathy is associated with aberrant DNA methylation in human amyotrophic lateral sclerosis</title><title>Neuropathology and applied neurobiology</title><addtitle>Neuropathol Appl Neurobiol</addtitle><description>Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neurone (MN) degeneration and death. ALS can be sporadic (sALS) or familial, with a number of associated gene mutations, including C9orf72 (C9ALS). DNA methylation is an epigenetic mechanism whereby a methyl group is attached to a cytosine (5mC), resulting in gene expression repression. 5mC can be further oxidized to 5‐hydroxymethylcytosine (5hmC). DNA methylation has been studied in other neurodegenerative diseases, but little work has been conducted in ALS. Aims To assess differences in DNA methylation in individuals with ALS and the relationship between DNA methylation and TDP43 pathology. Methods Post mortem tissue from controls, sALS cases and C9ALS cases were assessed by immunohistochemistry for 5mC and 5hmC in spinal cord, motor cortex and prefrontal cortex. LMNs were extracted from a subset of cases using laser capture microdissection. DNA from these underwent analysis using the MethylationEPIC array to determine which molecular processes were most affected. Results There were higher levels of 5mC and 5hmC in sALS and C9ALS in the residual lower motor neurones (LMNs) of the spinal cord. Importantly, in LMNs with TDP43 pathology there was less nuclear 5mC and 5hmC compared to the majority of residual LMNs that lacked TDP43 pathology. Enrichment analysis of the array data suggested RNA metabolism was particularly affected. Conclusions DNA methylation is a contributory factor in ALS LMN pathology. 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J.</creator><creator>Cooper‐Knock, J.</creator><creator>Heath, P. R.</creator><creator>Highley, J. R.</creator><general>Wiley Subscription Services, Inc</general><scope>24P</scope><scope>WIN</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4969-6526</orcidid><orcidid>https://orcid.org/0000-0002-7468-5917</orcidid></search><sort><creationdate>202102</creationdate><title>TDP43 proteinopathy is associated with aberrant DNA methylation in human amyotrophic lateral sclerosis</title><author>Appleby‐Mallinder, C. ; Schaber, E. ; Kirby, J. ; Shaw, P. J. ; Cooper‐Knock, J. ; Heath, P. R. ; Highley, J. R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3885-a7fc14bace28c3ef07f173d7f6266b0596bebc2e80574a1b2aa88bd15601d7433</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Amyotrophic lateral sclerosis</topic><topic>Cortex (motor)</topic><topic>Cytosine</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA hydroxymethylation</topic><topic>DNA methylation</topic><topic>Epigenetics</topic><topic>Gene expression</topic><topic>Immunohistochemistry</topic><topic>Motor neurone disease</topic><topic>Neurodegeneration</topic><topic>Neurodegenerative diseases</topic><topic>Neuronal-glial interactions</topic><topic>Pathology</topic><topic>Prefrontal cortex</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>Spinal cord</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Appleby‐Mallinder, C.</creatorcontrib><creatorcontrib>Schaber, E.</creatorcontrib><creatorcontrib>Kirby, J.</creatorcontrib><creatorcontrib>Shaw, P. J.</creatorcontrib><creatorcontrib>Cooper‐Knock, J.</creatorcontrib><creatorcontrib>Heath, P. R.</creatorcontrib><creatorcontrib>Highley, J. R.</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Wiley Online Library Free Content</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Neuropathology and applied neurobiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Appleby‐Mallinder, C.</au><au>Schaber, E.</au><au>Kirby, J.</au><au>Shaw, P. J.</au><au>Cooper‐Knock, J.</au><au>Heath, P. R.</au><au>Highley, J. R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TDP43 proteinopathy is associated with aberrant DNA methylation in human amyotrophic lateral sclerosis</atitle><jtitle>Neuropathology and applied neurobiology</jtitle><addtitle>Neuropathol Appl Neurobiol</addtitle><date>2021-02</date><risdate>2021</risdate><volume>47</volume><issue>1</issue><spage>61</spage><epage>72</epage><pages>61-72</pages><issn>0305-1846</issn><eissn>1365-2990</eissn><abstract>Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neurone (MN) degeneration and death. ALS can be sporadic (sALS) or familial, with a number of associated gene mutations, including C9orf72 (C9ALS). DNA methylation is an epigenetic mechanism whereby a methyl group is attached to a cytosine (5mC), resulting in gene expression repression. 5mC can be further oxidized to 5‐hydroxymethylcytosine (5hmC). DNA methylation has been studied in other neurodegenerative diseases, but little work has been conducted in ALS. Aims To assess differences in DNA methylation in individuals with ALS and the relationship between DNA methylation and TDP43 pathology. Methods Post mortem tissue from controls, sALS cases and C9ALS cases were assessed by immunohistochemistry for 5mC and 5hmC in spinal cord, motor cortex and prefrontal cortex. LMNs were extracted from a subset of cases using laser capture microdissection. DNA from these underwent analysis using the MethylationEPIC array to determine which molecular processes were most affected. Results There were higher levels of 5mC and 5hmC in sALS and C9ALS in the residual lower motor neurones (LMNs) of the spinal cord. Importantly, in LMNs with TDP43 pathology there was less nuclear 5mC and 5hmC compared to the majority of residual LMNs that lacked TDP43 pathology. Enrichment analysis of the array data suggested RNA metabolism was particularly affected. Conclusions DNA methylation is a contributory factor in ALS LMN pathology. This is not so for glia or neocortical neurones.</abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>32365404</pmid><doi>10.1111/nan.12625</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-4969-6526</orcidid><orcidid>https://orcid.org/0000-0002-7468-5917</orcidid><oa>free_for_read</oa></addata></record>
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subjects Amyotrophic lateral sclerosis
Cortex (motor)
Cytosine
Deoxyribonucleic acid
DNA
DNA hydroxymethylation
DNA methylation
Epigenetics
Gene expression
Immunohistochemistry
Motor neurone disease
Neurodegeneration
Neurodegenerative diseases
Neuronal-glial interactions
Pathology
Prefrontal cortex
Ribonucleic acid
RNA
Spinal cord
title TDP43 proteinopathy is associated with aberrant DNA methylation in human amyotrophic lateral sclerosis
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