Yeast Protein Could Offer Clues to How Alzheimer’s Plaques Form in the Brain

Biologists find unexpected role for amyloid-forming protein.

Fibrous protein clumps known as amyloids are most often associated with diseases such as Alzheimer’s disease, where they form characteristic plaques in the brain.

Scientists first described amyloids about 150 years ago; they have since been tagged as key players in Parkinson’s disease, Huntington’s disease, and rheumatoid arthritis, as well as Alzheimer’s. However, recent findings suggest that this class of proteins may also have critical biological functions in healthy cells.

In a study appearing in this week’s issue of Cell, MIT biologists have discovered that yeast cells need to build amyloid-like structures during the production of reproductive cells called spores. Learning more about how yeast build and then break down these protein structures could help scientists develop drugs that destroy disease-causing amyloids, the researchers say.

“Amyloids in the brain persist for decades. We just can’t get rid of them, yet yeast cells seem to have a mechanism for getting rid of them in 15 minutes,” says Luke Berchowitz, a postdoc at MIT’s Koch Institute for Integrative Cancer Research and the paper’s lead author. “If we can harness that mechanism, and really understand it, that could lead to anti-amyloid therapeutic opportunities.”

The paper’s senior author is Angelika Amon, the Kathleen and Curtis Marble Professor in Cancer Research and a member of the Koch Institute. Other authors are undergraduate Margaret Walker, postdocs Greg Kabachinski and Thomas Carlile, associate professor of biology Wendy Gilbert, and professor of biology Thomas Schwartz.

Reproductive role

Berchowitz and colleagues came across the yeast amyloid-forming protein known as Rim4 while investigating how sexual reproduction works in yeast. Rim4 is a protein containing long regions of disorder and stretches rich in the amino acid asparagine, which is a hallmark of a type of amyloid-forming proteins known as prions.

Berchowitz and Amon had previously discovered that Rim4 latches onto messenger RNA (mRNA) molecules, which carry genetic information to the cell’s protein-building machinery. In the new Cell paper, the researchers found that Rim4 uses amyloid-like clusters to prevent these mRNA molecules from being transcribed into proteins.

This process regulates the formation of spores — reproductive cells that are analogous to eggs and sperm, the researchers found.

Yeast usually reproduce asexually, through a process called budding, but under certain high-stress conditions, they can also undergo sexual reproduction through creation of spores that fuse to form new cells. The MIT team found that as yeast cells near completion of sexual reproduction, Rim4 amyloid-like clusters are broken down, releasing mRNA required for the cells to complete meiosis — the specialized type of cell division that produces spores.

“None of us anticipated that the way Rim4 actually works is by formation of these aggregates,” says Scott Keeney, a member of the Memorial Sloan Kettering Cancer Center, who was not involved in the research. “We’re used to thinking of these as toxic aggregates, so to demonstrate that they actually have a useful function in cells is intriguing.”

Image shows amyloid beta attacking a cell.
MIT biologists found that the yeast protein Rim4 forms disordered clumps similar to the beta-amyloid plaques associated with Alzheimer’s disease, shown here. Credit: NIH.

The researchers also found preliminary data suggesting that an amyloid protein known as DAZL plays the same role in sperm formation in mice; they believe that similar proteins are probably found in every organism that reproduces sexually, including humans.

Berchowitz says it is still unclear why cells rely on amyloid-forming proteins for this type of regulation, but one advantage amyloids offer is their ability to withstand the harsh environments in which sexual reproduction cells are formed. “Amyloids are stable and they’re able to sequester things,” he says. “They’re very tough guardians.”

“A great opportunity”

Previously, scientists have found a few other examples of amyloid-forming proteins that have critical roles in normal cell functions: In fruit flies, persistence of memory can rely on formation of amyloid-like structures in the brain, and amyloids are also involved in the formation of the skin pigment melanin in humans.

Learning more about how cells break down those amyloids could help scientists develop new drugs for disease such as Alzheimer’s, Parkinson’s, Huntington’s, and rheumatoid arthritis. Berchowitz is now working on figuring out how yeast cells regulate the breakdown of Rim4 aggregates.

“It’s a great opportunity to study assembly, regulation, and function of amyloids in living cells,” he says. “It’s pretty exciting that we can form them rapidly, synchronously, and abundantly.”

About this Alzheimer’s disease research

Source: Anne Trafton – MIT
Image Credit: The image is credited to the NIH and is in the public domain
Original Research: Abstract for “Regulated Formation of an Amyloid-like Translational Repressor Governs Gametogenesis” by Luke E. Berchowitz, Greg Kabachinski, Margaret R. Walker, Thomas M. Carlile, Wendy V. Gilbert, Thomas U. Schwartz, and Angelika Amon in Cell. Published online September 24 2015 doi:10.1016/j.cell.2015.08.060


Regulated Formation of an Amyloid-like Translational Repressor Governs Gametogenesis

•Amyloid-like aggregation of the RNA-binding protein Rim4 controls gametogenesis
•The amyloid-like form of Rim4 is active and represses translation
•Aggregation and clearance of Rim4 are developmentally regulated
•Amyloid-like aggregation of RNA-binding proteins during gametogenesis is conserved

Message-specific translational control is required for gametogenesis. In yeast, the RNA-binding protein Rim4 mediates translational repression of numerous mRNAs, including the B-type cyclin CLB3, which is essential for establishing the meiotic chromosome segregation pattern. Here, we show that Rim4 forms amyloid-like aggregates and that it is the amyloid-like form of Rim4 that is the active, translationally repressive form of the protein. Our data further show that Rim4 aggregation is a developmentally regulated process. Starvation induces the conversion of monomeric Rim4 into amyloid-like aggregates, thereby activating the protein to bring about repression of translation. At the onset of meiosis II, Rim4 aggregates are abruptly degraded allowing translation to commence. Although amyloids are best known for their role in the etiology of diseases such as Alzheimer’s, Parkinson’s, and diabetes by forming toxic protein aggregates, our findings show that cells can utilize amyloid-like protein aggregates to function as central regulators of gametogenesis.

“Regulated Formation of an Amyloid-like Translational Repressor Governs Gametogenesis” by Luke E. Berchowitz, Greg Kabachinski, Margaret R. Walker, Thomas M. Carlile, Wendy V. Gilbert, Thomas U. Schwartz, and Angelika Amon in Cell. Published online September 24 2015 doi:10.1016/j.cell.2015.08.060

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