11 Oct 2024

Frontotemporal dementia (FTD) often strikes our most human traits, such as the ability to speak and to interact on social and emotional levels. Now, research led by Lorenzo Pasquini and William Seeley at the University of California, San Francisco, suggests that rapidly evolving genes that helped shape the human brain might also make people vulnerable to FTD.

The study, published in the Sept. 3 Brain, investigated why subtypes of FTD target specific brain regions. It brought together three different types of data: regional gene expression across the brain; human-accelerated regions (HARs), which are sections of the genome that have changed rapidly as humans diverged from chimpanzees; and genes regulated by the DNA-binding protein TDP-43.

“All of a sudden it dawned on us that we needed to bring these three things together, because it might be that TDP-43 and human evolution are working hand in hand, and that the advancements that the HARs confer upon a human brain might also create trapdoors and liabilities,” said Seeley.

The project relied on data from 164 participants who donated their brains to the University of California, San Francisco (UCSF), Neurodegenerative Disease Brain Bank. All the participants had MRI scans while they were alive, and examination of their brains after death revealed degeneration typical of the most common types of FTD. In particular, all had had frontotemporal lobular degeneration (FTLD) characterized by aggregates of either TDP-43 or tau. First author Pasquini and colleagues could further divide the FTLD-TDP and FTLD-tau groups into five subtypes, each with distinct patterns of degeneration that start in different parts of the brain.

The scientists mapped out where brains showed the most atrophy in each FTLD subtype, then compared that to expression patterns of 20,734 genes in 273 regions across the left and right hemispheres of normal brains as documented in the Allen Human Brain Atlas. This revealed genes that are normally expressed at high or low levels in parts of the brain affected by each FTLD subtype. These atrophy-correlated genes are likely to play some role in the disease, so Pasquini focused on these for additional comparisons.  

The strongest findings emerged when he compared these genes with those that are thought to be important for the evolution of the human brain, namely genes containing human-accelerated regions. HARs are similar in most mammals but differ between humans and chimpanzees. Pasquini found that HAR genes overlapped with the atrophy-correlated genes far more than would be expected by chance. These HAR genes differed between FTLD subtypes, but all subtypes were enriched for HAR genes. The findings suggest that the evolution of HAR genes might have left the brain vulnerable to FTD pathology.

Gene overlaps. Human-accelerated regions, or HARs (top), are parts of the genome that are conserved in many species but have changed rapidly since humans diverged from chimpanzees. Of the 1,373 HAR genes examined, 808 were among the 8,276 genes whose expression correlated with atrophy in FTLD-TDP (bottom left). Likewise, expression of 560 HAR genes correlated with atrophy in FTLD-tau (bottom right). [Courtesy of Pasquini et al., 2024.)

Does this explain why other primates are less vulnerable to neurodegeneration, as some data suggest? Scientists have long suspected that evolutionary changes responsible for humans’ unique cognitive abilities might also make us prone to disease. But while HAR genes have been implicated previously in neuropsychiatric and neurodevelopmental disorders such as autism spectrum disorder and schizophrenia, this is the first time their regional expression has been linked to a neurodegenerative disorder (Guardiola-Ripoll and Fatjó-Vilas, 2023).

Seeley said he was excited to see associations between recently evolved genes and FTD, even though he would have been surprised if his team had not found them. “FTD is a frontal and anterior brain disease, and we have always thought that the human ecological niche has put more pressure on those areas of the brain than on others,” he said.

To dig more deeply into the roots of FTLD, the researchers ran additional comparisons with genes that are mis-spliced when TDP-43 stops working. This normally nuclear protein regulates gene expression, binding to pre-RNA and shielding certain splice junctions. When TDP-43 aggregates and gets trapped in the cytosol, introns are mistakenly spliced into mRNAs, forming “cryptic exons” that can ruin the translated protein (Seddighi et al., 2023). This TDP-43 pathology occurs in a range of neurodegenerative conditions, but it's still unclear how important cryptic splicing is relative to toxicity from the TDP-43 aggregates themselves, said Seeley.

The researchers compared 257 genes that are expressed in the brain and undergo cryptic splicing with the genes whose regional expression correlated with FTLD-TDP. One hundred forty-six genes appeared on both lists, which was no more than expected by chance. However, it was significantly more than the 88 cryptic splicing genes that overlapped with the FTLD-tau group.

That genes subject to cryptic splicing were more strongly associated with FTLD-TDP than they were with FTLD-tau suggests that the loss of TDP-43’s regulatory function may indeed be important, and the overlapping genes are worth looking at further, said Seeley.

Do any of these cryptic splicing genes harbor HARs? Indeed, Pasquini found that 37 genes that were susceptible to such splicing, and had expression patterns that correlate with at least one subtype of FTLD-TDP, were also HAR genes, supporting the idea that FTD affects brain regions that have become particularly vulnerable because of evolutionary pressure.

The study offered rare insight into one of the great mysteries of neurodegenerative disease: the problem of selective vulnerability, said Lary Walker, professor emeritus at Emory University in Atlanta, who was not involved in the research. Walker thinks the scientists had the right approach in using genetics to understand why different parts of the brain are selectively vulnerable to different types of neurodegeneration.

“There's something different about cells that are affected either earliest or most intensely in these diseases. And if we can figure that out, there may be molecular targets for therapeutic approaches that we weren't aware of before,” he said.

Peter Nelson of the University of Kentucky in Lexington cautioned that the gene-expression data from the Allen Human Brain Atlas were based on a limited sample: only two whole brains and four left hemispheres. Nevertheless, Nelson praised the work for investigating the roles of many genes at once, using approaches that could grapple with the true complexity of neurodegenerative disease.

“Our puny human brains like to think of there being one gene or two genes in a network that are interesting. And [the authors] thought, ‘To hell with that. There are dozens of genes that are relevant.’ And it's their orchestration that both enables us to be functional, but also contributes to dysfunction,” said Nelson, who was not involved in the study.

Still, for the next steps, Seeley and his colleagues are narrowing their focus to the FTLD-TDP-correlated HAR genes that can be cryptically spliced.

“Those 37 genes are the most interesting product of the research,” said Seeley. “We're looking at that list really carefully, and trying to take it into tissue studies and see what we can learn.”—Nala Rogers

Nala Rogers is a freelance writer in Silver Spring, Maryland.

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References

Paper Citations

1. Guardiola-Ripoll M, Fatjó-Vilas M. A Systematic Review of the Human Accelerated Regions in Schizophrenia and Related Disorders: Where the Evolutionary and Neurodevelopmental Hypotheses Converge. Int J Mol Sci. 2023 Feb 10;24(4) PubMed.
2. Seddighi S, Qi YA, Brown AL, Wilkins OG, Bereda C, Belair C, Zhang Y, Prudencio M, Keuss MJ, Khandeshi A, Pickles S, Hill SE, Hawrot J, Ramos DM, Yuan H, Roberts J, Sacramento EK, Shah SI, Nalls MA, Colon-Mercado J, Reyes JF, Ryan VH, Nelson MP, Cook C, Li Z, Screven L, Kwan JY, Shantaraman A, Ping L, Koike Y, Oskarsson BR, Staff N, Duong DM, Ahmed A, Secrier M, Ule J, Jacobson S, Rohrer J, Malaspina A, Glass JD, Ori A, Seyfried NT, Maragkakis M, Petrucelli L, Fratta P, Ward ME. Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD. bioRxiv. 2023 Jan 23; PubMed.

Further Reading

Papers

1. Barnes CA, Permenter MR, Vogt JA, Chen K, Beach TG. Human Alzheimer's Disease ATN/ABC Staging Applied to Aging Rhesus Macaque Brains: Association With Cognition and MRI-Based Regional Gray Matter Volume. J Comp Neurol. 2024 Sep;532(9):e25670. PubMed.