Protein Discovery New Key to Memory Formation

Summary: Researchers discovered a surprising new function of the protein RPT6 in the brain, which could revolutionize the understanding and treatment of memory disorders.

Previously known for its role in the proteasome complex in the hippocampus, RPT6 has now been found to bind to DNA and regulate gene expression during memory formation.

This dual functionality of RPT6 offers new insights into the intricate process of memory formation and holds potential for therapeutic interventions in conditions like Alzheimer’s disease and PTSD.

Key Facts:

1. RPT6 has been identified to have a dual role: it’s part of the proteasome complex and also regulates gene expression during memory formation.
2. This discovery provides new insights into memory processes, potentially leading to better treatments for memory disorders.
3. The study by Virginia Tech could significantly impact future research on Alzheimer’s, dementia, PTSD, and other memory-related conditions.

Source: Virginia Tech

Virginia Tech researchers discovered a new function for a common protein in the brain — a development that sheds new light on the mysteries of the mind and holds promising implications for the treatment of memory loss and post-traumatic stress disorder.

The protein normally performs necessary housekeeping in the brain’s hippocampus by working as part of a larger protein complex called the proteasome to destroy other proteins.

But researchers in the College of Agriculture and Life Sciences’ School of Animal Sciences recently noticed this protein, called RPT6, behaving in a previously undetected way. 

“We found that RPT6 is capable of this completely different function where it can bind to DNA and increase the expression of other genes or proteins during memory formation,” said Tim Jarome,  associate professor of neurobiology. “This indicates that RPT6 plays a unique dual role in memory formation, both inside and outside the proteasome complex.”

The discovery, published this month in the Journal of Neuroscience, opens up new avenues for exploration of how RPT6 functions in the brain and how it could be manipulated to improve memory and alleviate memory disorders such as Alzheimer’s disease and post-traumatic stress disorder (PTSD).

The project was led by research scientist Kayla Farrell, who received her Ph.D. from the School of Animal Sciences in December. Farrell previously headed a study identifying a protein that could lead to better therapeutic treatment for women with PTSD.

Gene expression is critical to memory formation. It helps to build the neural networks needed to form and strengthen memories. Researchers don’t yet understand why RPT6 has this dual function or how it is helping to control the cells that are recruited to form a memory. 

“There has to be something else that’s working with it to regulate gene expression,” Jarome said. “We are trying to understand now how it’s doing that.”

Ultimately, the discovery will be helpful to the ongoing research in Jarome’s lab, which focuses on understanding and treating memory disorders such as Alzheimer’s, dementia, and PTSD.

“This discovery is leading us somewhere new in unraveling the complexities of the brain and how we learn and store memories,” Jarome said. “We hope that this will help to inform new directions into understanding how gene expression is controlled during memory. In the long-term, this could lead to potential therapeutic targets for controlling and improving memory or treating maladaptive memories.”

Key findings

• Dual function of RPT6: RPT6, a protein found in every cell, was previously known for its role within the proteasome complex. The study reveals that during memory formation, RPT6 can also bind to DNA and regulate gene expression, presenting a unique dual functionality.
• Implications for memory manipulation: Understanding the dual role of RPT6 provides insights into the complex processes of memory formation. This knowledge could pave the way for targeted therapeutic interventions to enhance memory or alleviate negative memories associated with conditions such as PTSD.
• Significance for future research: The study marks a crucial step in unraveling the complexities of the brain and gene expression control during memory formation. Researchers anticipate that further investigation into RPT6’s mechanisms will inform new directions for understanding memory at the molecular level.

About this memory research news

Author: Margaret Ashburn
Source: Virginia Tech
Contact: Margaret Ashburn – Virginia Tech
Image: The image is credited to Neuroscience News

Original Research: Closed access.
“Phosphorylation of RPT6 Controls Its Ability to Bind DNA and Regulate Gene Expression in the Hippocampus of Male Rats during Memory Formation” by Tim Jarome et al. Journal of Neuroscience

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Abstract

Phosphorylation of RPT6 Controls Its Ability to Bind DNA and Regulate Gene Expression in the Hippocampus of Male Rats during Memory Formation

Memory formation requires coordinated control of gene expression, protein synthesis, and ubiquitin–proteasome system (UPS)-mediated protein degradation. The catalytic component of the UPS, the 26S proteasome, contains a 20S catalytic core surrounded by two 19S regulatory caps, and phosphorylation of the 19S cap regulatory subunit RPT6 at serine 120 (pRPT6-S120) has been widely implicated in controlling activity-dependent increases in proteasome activity.

Recently, RPT6 was also shown to act outside the proteasome where it has a transcription factor-like role in the hippocampus during memory formation. However, little is known about the proteasome-independent function of “free” RPT6 in the brain or during memory formation and whether phosphorylation of S120 is required for this transcriptional control function.

Here, we used RNA-sequencing along with novel genetic approaches and biochemical, molecular, and behavioral assays to test the hypothesis that pRPT6-S120 functions independently of the proteasome to bind DNA and regulate gene expression during memory formation. RNA-sequencing following siRNA-mediated knockdown of free RPT6 revealed 46 gene targets in the dorsal hippocampus of male rats following fear conditioning, where RPT6 was involved in transcriptional activation and repression.

Through CRISPR-dCas9-mediated artificial placement of RPT6 at a target gene, we found that RPT6 DNA binding alone may be important for altering gene expression following learning.

Further, CRISPR-dCas13-mediated conversion of S120 to glycine on RPT6 revealed that phosphorylation at S120 is necessary for RPT6 to bind DNA and properly regulate transcription during memory formation.

Together, we reveal a novel function for phosphorylation of RPT6 in controlling gene transcription during memory formation.