Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation in specific brain regions is associated with declines in human-specialized social-emotional and language functions. In most patients, disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we...

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Autores: Pasquini, L, Pereira, FL, Seddighi, S, Zeng, Y, Wei, YB, Illán-Gala, I, Vatsavayai, SC, Friedberg, A, Lee, AJ, Brown, JA, Spina, S, Grinberg, LT, Sirkis, DW, Bonham, LW, Yokoyama, JS, Boxer, AL, Kramer, JH, Rosen, HJ, Humphrey, J, Gitler, AD, Miller, BL, Pollard, KS, Ward, ME, Seeley, WW
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2024
País:España
Recursos:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositório:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p18668
Acesso em linha:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=18668
https://ddd.uab.cat/record/324031
Access Level:Acceso aberto
Palavra-chave:frontotemporal lobar degeneration
cryptic exon
human accelerated regions
TDP-43
tau
gene expression
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spelling Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genesPasquini, LPereira, FLSeddighi, SZeng, YWei, YBIllán-Gala, IVatsavayai, SCFriedberg, ALee, AJBrown, JASpina, SGrinberg, LTSirkis, DWBonham, LWYokoyama, JSBoxer, ALKramer, JHRosen, HJHumphrey, JGitler, ADMiller, BLPollard, KSWard, MESeeley, WWfrontotemporal lobar degenerationcryptic exonhuman accelerated regionsTDP-43taugene expressionIn frontotemporal lobar degeneration (FTLD), pathological protein aggregation in specific brain regions is associated with declines in human-specialized social-emotional and language functions. In most patients, disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD-associated regional degeneration patterns relate to regional gene expression of human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution.To this end, we used structural neuroimaging from patients with FTLD and human brain regional transcriptomic data from controls to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions linked to expression levels of recently evolved genes. In addition, we asked whether genes whose expression correlates with FTLD atrophy are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired.We found that FTLD-TDP and FTLD-tau subtypes target brain regions with overlapping and distinct gene expression correlates, highlighting many genes linked to neuromodulatory functions. FTLD atrophy-correlated genes were strongly enriched for HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes and genes with more numerous TDP-43 binding sites compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes.Overall, our findings suggest that FTLD targets brain regions that have undergone recent evolutionary specialization and provide intriguing potential leads regarding the transcriptomic basis for selective vulnerability in distinct FTLD molecular-anatomical subtypes. Frontotemporal lobar degeneration (FTLD) erodes brain functions that have evolved relatively recently in humans, such as language and social behaviour. Pasquini et al. explore whether brain regions targeted by FTLD are linked to expression of genes that have undergone positive selection during human evolution.OXFORD UNIV PRESS2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=18668https://ddd.uab.cat/record/324031BRAINISSN: 00068950ISSNe: 14602156reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p186682026-06-14T12:41:47Z
dc.title.none.fl_str_mv Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes
title Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes
spellingShingle Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes
Pasquini, L
frontotemporal lobar degeneration
cryptic exon
human accelerated regions
TDP-43
tau
gene expression
title_short Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes
title_full Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes
title_fullStr Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes
title_full_unstemmed Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes
title_sort Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes
dc.creator.none.fl_str_mv Pasquini, L
Pereira, FL
Seddighi, S
Zeng, Y
Wei, YB
Illán-Gala, I
Vatsavayai, SC
Friedberg, A
Lee, AJ
Brown, JA
Spina, S
Grinberg, LT
Sirkis, DW
Bonham, LW
Yokoyama, JS
Boxer, AL
Kramer, JH
Rosen, HJ
Humphrey, J
Gitler, AD
Miller, BL
Pollard, KS
Ward, ME
Seeley, WW
author Pasquini, L
author_facet Pasquini, L
Pereira, FL
Seddighi, S
Zeng, Y
Wei, YB
Illán-Gala, I
Vatsavayai, SC
Friedberg, A
Lee, AJ
Brown, JA
Spina, S
Grinberg, LT
Sirkis, DW
Bonham, LW
Yokoyama, JS
Boxer, AL
Kramer, JH
Rosen, HJ
Humphrey, J
Gitler, AD
Miller, BL
Pollard, KS
Ward, ME
Seeley, WW
author_role author
author2 Pereira, FL
Seddighi, S
Zeng, Y
Wei, YB
Illán-Gala, I
Vatsavayai, SC
Friedberg, A
Lee, AJ
Brown, JA
Spina, S
Grinberg, LT
Sirkis, DW
Bonham, LW
Yokoyama, JS
Boxer, AL
Kramer, JH
Rosen, HJ
Humphrey, J
Gitler, AD
Miller, BL
Pollard, KS
Ward, ME
Seeley, WW
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv frontotemporal lobar degeneration
cryptic exon
human accelerated regions
TDP-43
tau
gene expression
topic frontotemporal lobar degeneration
cryptic exon
human accelerated regions
TDP-43
tau
gene expression
description In frontotemporal lobar degeneration (FTLD), pathological protein aggregation in specific brain regions is associated with declines in human-specialized social-emotional and language functions. In most patients, disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD-associated regional degeneration patterns relate to regional gene expression of human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution.To this end, we used structural neuroimaging from patients with FTLD and human brain regional transcriptomic data from controls to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions linked to expression levels of recently evolved genes. In addition, we asked whether genes whose expression correlates with FTLD atrophy are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired.We found that FTLD-TDP and FTLD-tau subtypes target brain regions with overlapping and distinct gene expression correlates, highlighting many genes linked to neuromodulatory functions. FTLD atrophy-correlated genes were strongly enriched for HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes and genes with more numerous TDP-43 binding sites compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes.Overall, our findings suggest that FTLD targets brain regions that have undergone recent evolutionary specialization and provide intriguing potential leads regarding the transcriptomic basis for selective vulnerability in distinct FTLD molecular-anatomical subtypes. Frontotemporal lobar degeneration (FTLD) erodes brain functions that have evolved relatively recently in humans, such as language and social behaviour. Pasquini et al. explore whether brain regions targeted by FTLD are linked to expression of genes that have undergone positive selection during human evolution.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=18668
https://ddd.uab.cat/record/324031
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=18668
https://ddd.uab.cat/record/324031
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv OXFORD UNIV PRESS
publisher.none.fl_str_mv OXFORD UNIV PRESS
dc.source.none.fl_str_mv BRAIN
ISSN: 00068950
ISSNe: 14602156
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
repository.name.fl_str_mv
repository.mail.fl_str_mv
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