FTLD targets brain regions expressing recently evolved genes
Pasquini, Lorenzo (University of California San Francisco)
Pereira, Felipe L. (University of California)
Seddighi, Sahba (National Institute of Neurological Disorders and Stroke)
Zeng, Yi (Stanford University School of Medicine)
Wei, Yongbin (Beijing University of Posts and Telecommunications)
Illán-Gala, Ignacio (Institut d'Investigació Biomèdica Sant Pau)
Vatsavayai, Sarat C. (University of California)
Friedberg, Adit (University of California)
Lee, Alex J. (University of California)
Brown, Jesse A. (University of California)
Spina, Salvatore (University of California)
Grinberg, Lea T. (University of California)
Sirkis, Daniel W. (University of California)
Bonham, Luke W. (University of California)
Yokoyama, Jennifer S. (University of California)
Boxer, Adam L. (University of California)
Kramer, Joel H. (University of California)
Rosen, Howard J. (University of California)
Humphrey, Jack (Icahn School of Medicine at Mount Sinai)
Gitler, Aaron D. (Stanford University School of Medicine)
Miller, Bruce L. (University of California)
Pollard, Katherine S. (Chan Zuckerberg Biohub)
Ward, Michael E. (National Institute of Neurological Disorders and Stroke)
Seeley, William W. (University of California San Francisco)
Universitat Autònoma de Barcelona

Data:	2023
Resum:	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.
Ajuts:	Instituto de Salud Carlos III PI21/00791
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Cryptic exon ; Frontotemporal lobar degeneration ; Gene expression ; Human accelerated regions ; Tau ; TDP-43
Publicat a:	medRxiv, october 2023

DOI: 10.1101/2023.10.27.23297687
PMID: 37961381

39 p, 1.1 MB

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