Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes
Wei, Y. (Beijing University of Posts and Telecommunications)
Illán-Gala, Ignacio (Institut de Recerca Sant Pau)
Spina, S. (University of California)
Grinberg, L.T. (Department of Pathology. University of California)
Yokoyama, Jennifer S. (University of California)
Boxer, A.L. (University of California)
Kramer, J.H. (University of California)
Rosen, H.J. (University of California)
Miller, B.L. (University of California)
Seeley, W.W. (University of California)
Pasquini, L. (University of California)
Pereira, F.L. (University of California)
Seddighi, S. (National Institute of Neurological Disorders and Stroke. Neurogenetics Branch)
Zeng, Y. (Stanford University)
Vatsavayai, S.C. (University of California)
Friedberg, A. (University of California)
Lee, A.J. (University of California)
Brown, J.A. (University of California)
Sirkis, D.W. (University of California)
Bonham, L.W. (University of California)
Humphrey, J. (Icahn School of Medicine at Mount Sinai (Nova York, Estats Units d'Amèrica))
Gitler, A.D. (Stanford University)
Pollard, K.S. (Chan Zuckerberg Biohub)
Ward, M.E. (National Institute of Neurological Disorders and Stroke. Neurogenetics Branch)
Universitat Autònoma de Barcelona. Departament de Medicina

Data:	2024
Resum:	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.
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, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	TDP-43 ; cryptic exon ; frontotemporal lobar degeneration; gene expression ; human accelerated regions ; tau
Publicat a:	Brain, Vol. 147, Num. 9 (September 2024) , p. 3032-3047, ISSN 1460-2156

DOI: 10.1093/brain/awae205
PMID: 38940350

16 p, 1.5 MB

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