FTLD targets brain regions expressing recently evolved genes.

Frontotemporal lobar degeneration TDP-43 cryptic exon gene expression human accelerated regions tau

Journal

medRxiv : the preprint server for health sciences
Titre abrégé: medRxiv
Pays: United States
ID NLM: 101767986

Informations de publication

Date de publication:
28 Oct 2023
Historique:
pubmed: 14 11 2023
medline: 14 11 2023
entrez: 14 11 2023
Statut: epublish

Résumé

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation is associated with a decline in human-specialized social-emotional and language functions. Most disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD targets brain regions that express genes containing 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 normative human regional transcriptomic data 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 expressing recently evolved genes. In addition, we asked whether genes expressed in FTLD-targeted brain regions 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 that express overlapping and distinct genes, including many linked to neuromodulatory functions. Genes whose normative brain regional expression pattern correlated with FTLD cortical atrophy were strongly associated with HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes 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.

Identifiants

DOI: 10.1101/2023.10.27.23297687 PMID: 37961381 PMC: PMC10635220
pubmed: 37961381
doi: 10.1101/2023.10.27.23297687
pmc: PMC10635220
pii:
doi:

Types de publication

Preprint

Langues

eng

Déclaration de conflit d'intérêts

Competing interests The authors declare no competing interests.

Auteurs

Lorenzo Pasquini (L)

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Department of Neurology, Neuroscape, University of California, San Francisco, CA, USA.

Felipe L Pereira (FL)

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.

Sahba Seddighi (S)

National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.

Yi Zeng (Y)

Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.

Yongbin Wei (Y)

School of Artificial Intelligence, Beijing University of Posts and Telecommunications, Beijing, China.

Ignacio Illán-Gala (I)

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Global Brain Health Institute, University of California, San Francisco, San Francisco, CA, USA and Trinity College Dublin, Dublin, Ireland.
Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute, Universitat Autònoma de Barcelona, Barcelona, Catalunya, Spain.

Sarat C Vatsavayai (SC)

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.

Adit Friedberg (A)

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Global Brain Health Institute, University of California, San Francisco, San Francisco, CA, USA and Trinity College Dublin, Dublin, Ireland.

Alex J Lee (AJ)

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.

Jesse A Brown (JA)

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.

Salvatore Spina (S)

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.

Lea T Grinberg (LT)

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Department of Pathology, University of California, San Francisco, CA, USA.

Daniel W Sirkis (DW)

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.

Luke W Bonham (LW)

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Department of Radiology, University of California, San Francisco, CA, USA.

Jennifer S Yokoyama (JS)

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Department of Radiology, University of California, San Francisco, CA, USA.

Adam L Boxer (AL)

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.

Joel H Kramer (JH)

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.

Howard J Rosen (HJ)

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.

Jack Humphrey (J)

Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Aaron D Gitler (AD)

Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.

Bruce L Miller (BL)

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.

Katherine S Pollard (KS)

Gladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA.
Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
Department of Epidemiology & Biostatistics and Bakar Institute for Computational Health Sciences, University of California San Francisco, San Francisco, CA, USA.
Chan Zuckerberg Biohub, San Francisco, CA, USA.

Michael E Ward (ME)

National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.

William W Seeley (WW)

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Department of Pathology, University of California, San Francisco, CA, USA.

Classifications MeSH