Enzymes could be key for brain cancer and Alzheimer’s disease

| Written by Guest Blogger
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This post was written by Janelle Weaver, Ph.D., a freelance writer.

Animals ranging from fish to humans produce a vitamin-A metabolite called retinoic acid, which plays an important role in growth and embryonic development and protects against diseases such as cancer. By regulating the activity of key genes, retinoic acid causes immature cells called embryonic stem cells to turn into mature, specialized cells such as neurons. “Neurons—the building blocks of the nervous system—are particularly important cell types in therapy, due to the fact that they normally don’t reproduce or replace themselves after they become damaged,” said Laszlo Nagy, M.D., Ph.D., director of the Genomic Control of Metabolism Program and professor in the Diabetes and Obesity Research Center at Sanford-Burnham's Lake Nona campus. “Despite their crucial role, we still have a limited understanding regarding the molecular programs that coordinate their functionality.”

Addressing this gap in knowledge, Nagy and his team recently discovered that enzymes called protein arginine methyl transferases (PRMTs) 1 and 8 play key roles in regulating the effects of retinoic acid on gene activity and cellular specification. As reported  in the journal Stem Cells, PRMT1 reduces the potency of retinoic acid signals, whereas PRMT8 enhances retinoid signaling during later stages of differentiation of mouse embryonic stem cells to neurons. The researchers also found that PRMT8 is almost entirely absent in brain tissues from patients with glioblastoma—a fast-growing type of tumor that forms from glial cells, which make up the supportive tissue of the brain and spinal cord.

“The results of this study suggest a novel mechanism of how two evolutionarily linked proteins with similar enzymatic activity can have distinct effects on cellular differentiation through the integration of retinoid signaling,” Nagy said. “These proteins might be important in the development of neurodegenerative diseases such as Alzheimer’s disease, and they can be potential targets in the treatment of brain tumors.”

Balancing act The PRMT family of enzymes catalyzes arginine methylation—a chemical process involving the addition of a methyl group to an amino acid called arginine. The resulting arginine-methylated proteins are involved in a number of different cellular processes, including transcriptional regulation and DNA damage repair. Arginine methylation is also associated with cellular differentiation, but the role of PRMTs in the birth of neurons has not been clear.

In the new study, Nagy and his team set out to explore the involvement of PRMTs and arginine methylation in neuronal development using a multistage differentiation model of mouse embryonic stem cells to neurons. They found that PRMT1 levels were steady during the course of neuronal differentiation induced by treatment with retinoic acid. By contrast, PRMT8 was present only in mature, differentiated neurons. Moreover, cells that were depleted of PRMT1 were able to develop into mature cells such as neurons and heart-muscle cells, suggesting that cellular differentiation can occur in the absence of PRMT1. While retinoic acid-dependent transcriptional activity was markedly increased in the absence of PRMT1, loss of PRMT8 had an inhibitory effect on the retinoid response. These findings suggest that PRMT8 is a general co-activator of retinoic acid signaling, whereas PRMT1 arms the cells with a negative-feedback mechanism to limit the effects of retinoic acid on a subset of target genes.

“Our results suggest that PRMT1 and PRMT8 are not essential for early neural differentiation, but more likely play a role in its fine-tuning mechanism,” said lead study author Zoltan Simandi of the University of Debrecen in Hungary. “These fine-tuning mechanisms are even more important than dramatic effects, since they are tolerated during embryonic development and probably contribute to neurological diseases in adults.”

Therapeutic targets When the researchers analyzed brain tissues from patients with glioblastoma, they found a substantial reduction in the expression level of PRMT8, while PRMT1 expression was normal. These data indicate that loss of PRMT8 and genes regulated by it are putative markers in glioblastoma and might participate in its development. Moreover, their analysis suggests that PRMT1 and PRMT8 could affect molecular pathways related to Alzheimer’s disease.

“We are excited to understand in more detail the role of these proteins in healthy individuals as well as patients,” Nagy said. “In collaboration with clinicians, one of our future goals is to determine how PRMT8 contributes to the development of brain tumors and whether it can be used to improve diagnosis at earlier stages. Ultimately, we also hope to determine whether PRMT1 and PRMT8 can be targeted pharmacologically to modulate neuronal differentiation for the treatment of brain tumors or Alzheimer’s disease.”

The paper can be found at http://onlinelibrary.wiley.com/doi/10.1002/stem.1894/abstract.

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