Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes
Por:
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
Publicada:
27 ago 2024
Ahead of Print:
1 ago 2024
Resumen:
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.
Filiaciones:
Pasquini, L:
Univ Calif San Francisco, Memory & Aging Ctr, Dept Neurol, 675 Nelson Rising Ln, San Francisco, CA 94158 USA
Univ Calif San Francisco, Dept Neurol, Neuroscape, San Francisco, CA 94158 USA
Pereira, FL:
Univ Calif San Francisco, Memory & Aging Ctr, Dept Neurol, 675 Nelson Rising Ln, San Francisco, CA 94158 USA
Seddighi, S:
NINDS, Neurogenet Branch, Bethesda, MD 20892 USA
Zeng, Y:
Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA
Wei, YB:
Beijing Univ Posts & Telecommun, Sch Artificial Intelligence, Beijing 100876, Peoples R China
Illán-Gala, I:
Univ Calif San Francisco, Memory & Aging Ctr, Dept Neurol, 675 Nelson Rising Ln, San Francisco, CA 94158 USA
Univ Calif San Francisco, Global Brain Hlth Inst, San Francisco, CA 94158 USA
Trinity Coll Dublin, Dublin D02 X9W9, Ireland
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Biomed Res Inst, Dept Neurol, Barcelona 08041, Catalunya, Spain
Vatsavayai, SC:
Univ Calif San Francisco, Memory & Aging Ctr, Dept Neurol, 675 Nelson Rising Ln, San Francisco, CA 94158 USA
Friedberg, A:
Univ Calif San Francisco, Memory & Aging Ctr, Dept Neurol, 675 Nelson Rising Ln, San Francisco, CA 94158 USA
Univ Calif San Francisco, Global Brain Hlth Inst, San Francisco, CA 94158 USA
Trinity Coll Dublin, Dublin D02 X9W9, Ireland
Lee, AJ:
Univ Calif San Francisco, Memory & Aging Ctr, Dept Neurol, 675 Nelson Rising Ln, San Francisco, CA 94158 USA
Brown, JA:
Univ Calif San Francisco, Memory & Aging Ctr, Dept Neurol, 675 Nelson Rising Ln, San Francisco, CA 94158 USA
Spina, S:
Univ Calif San Francisco, Memory & Aging Ctr, Dept Neurol, 675 Nelson Rising Ln, San Francisco, CA 94158 USA
Grinberg, LT:
Univ Calif San Francisco, Memory & Aging Ctr, Dept Neurol, 675 Nelson Rising Ln, San Francisco, CA 94158 USA
Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94158 USA
Sirkis, DW:
Univ Calif San Francisco, Memory & Aging Ctr, Dept Neurol, 675 Nelson Rising Ln, San Francisco, CA 94158 USA
Bonham, LW:
Univ Calif San Francisco, Memory & Aging Ctr, Dept Neurol, 675 Nelson Rising Ln, San Francisco, CA 94158 USA
Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94158 USA
Yokoyama, JS:
Univ Calif San Francisco, Memory & Aging Ctr, Dept Neurol, 675 Nelson Rising Ln, San Francisco, CA 94158 USA
Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94158 USA
Boxer, AL:
Univ Calif San Francisco, Memory & Aging Ctr, Dept Neurol, 675 Nelson Rising Ln, San Francisco, CA 94158 USA
Kramer, JH:
Univ Calif San Francisco, Memory & Aging Ctr, Dept Neurol, 675 Nelson Rising Ln, San Francisco, CA 94158 USA
Rosen, HJ:
Univ Calif San Francisco, Memory & Aging Ctr, Dept Neurol, 675 Nelson Rising Ln, San Francisco, CA 94158 USA
Humphrey, J:
Icahn Sch Med Mt Sinai, Nash Family Dept Neurosci, New York, NY 10029 USA
Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA
Gitler, AD:
Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA
Miller, BL:
Univ Calif San Francisco, Memory & Aging Ctr, Dept Neurol, 675 Nelson Rising Ln, San Francisco, CA 94158 USA
Pollard, KS:
Gladstone Inst Data Sci & Biotechnol, San Francisco, CA 94158 USA
Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94158 USA
Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94158 USA
Univ Calif San Francisco, Bakar Inst Computat Hlth Sci, San Francisco, CA 94158 USA
Chan Zuckerberg Biohub, San Francisco, CA 94158 USA
Ward, ME:
NINDS, Neurogenet Branch, Bethesda, MD 20892 USA
Seeley, WW:
Univ Calif San Francisco, Memory & Aging Ctr, Dept Neurol, 675 Nelson Rising Ln, San Francisco, CA 94158 USA
Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94158 USA
Green Published, hybrid
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