Human evolution offers clues to frontotemporal dementia

October 11, 2024

Frontotemporal dementia (FTD) often affects our most human traits, such as the ability to speak and interact socially and emotionally. 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 may also make people vulnerable to FTD.

The study, published in Brain on September 3, investigated why subtypes of FTD target specific regions of the brain. He gathered three different types of data: regional gene expression throughout 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.

“Suddenly we realized that we had to bring these three things together, because it may be that TDP-43 and human evolution are working hand in hand, and that the advances that HARs confer on the human brain could also create trapdoors and liabilities,” Seeley said.

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

The scientists mapped where the brains showed the most atrophy in each FTLD subtype, and then compared this with expression patterns of 20,734 genes in 273 regions of the left and right hemispheres of the normal brain, as documented in the Atlas of Allen’s human brain. This revealed genes that are typically expressed at high or low levels in the 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 further comparisons.

The most compelling findings came when he compared these genes to those thought to be important for the evolution of the human brain—genes that contain human-accelerated regions. HARs are similar in most mammals, but differ between humans and chimpanzees. Pasquini found that HAR genes overlapped with genes correlated with atrophy 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 may have left the brain vulnerable to FTD pathology.

Genes overlap. Human-accelerated regions, or HARs (above), are parts of the genome that are conserved in many species but have changed rapidly since humans split 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). Similarly, 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 the evolutionary changes responsible for humans’ unique cognitive abilities might also make us prone to disease. But while HAR genes have previously been implicated in neuropsychiatric and neurodevelopmental disorders such as autism spectrum disorder and schizophrenia, this is the first time that 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 newly evolved genes and FTD, although he would have been surprised if his team hadn’t found them. “FTD is a frontal and anterior brain disease, and we’ve always thought that the human ecological niche has put more pressure on those areas of the brain than others,” he said.

To dig deeper into the roots of FTLD, the researchers made additional comparisons with genes that are mis-spliced ​​when TDP-43 stops working. This normally nuclear protein regulates gene expression, binds to pre-RNA and protects certain splice junctions. When TDP-43 aggregates and becomes trapped in the cytosol, introns are mistakenly spliced ​​into mRNA, forming “cryptic exons” that can ruin the translated protein (Seddighi et al., 2023). This TDP-43 pathology occurs in a number of neurodegenerative conditions, but the importance of cryptic splicing in relation to the toxicity of TDP-43 aggregates itself is still unclear, Seeley said.

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

The fact that genes subject to cryptic splicing were more strongly associated with FTLD-TDP than with FTLD-tau suggests that the loss of TDP-43 regulatory function may be important, and is worth looking into further. the overlapping genes, Seeley said.

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

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

“There is something different about the cells that are affected sooner or more 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 was based on a limited sample: just two whole brains and four left hemispheres. However, Nelson praised the work for investigating the roles of many genes at once, using approaches that could grapple with the true complexity of neurodegenerative diseases.

“Our little human brains like to think there are one 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 allows 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 colleagues are narrowing their focus to FTLD-TDP-correlated HAR genes that can be cryptically spliced.

“These 37 genes are the most interesting product of the research,” Seeley said. “We’re looking at this list very carefully and trying to incorporate it into tissue studies and see what we can learn.” – Nala Rogers

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