Genetics Protein Memoryneuroscience

Summary: Researchers have 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 proteasome assembly in the hippocampus, RPT6 now binds to DNA and regulates gene expression during memory formation.

This dual function of RPT6 provides new insights into the complex process of memory formation and has potential for therapeutic intervention in conditions such as Alzheimer’s disease and PTSD.

Key facts:

  1. RPT6 has been identified as having a dual role: it is part of a protein complex and also regulates gene expression during memory formation.
  2. This discovery provides new insights into memory processes, which may lead to better treatments for memory disorders.
  3. The research at Virginia Tech could greatly impact future research into Alzheimer’s, dementia, PTSD and other memory-related conditions.

Source: Virginia Tech

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

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

But researchers at the School of Animal Sciences in the College of Agriculture and Life Sciences recently noticed that this protein, called RPT6, moves in a previously unknown way.

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

The findings were published this month by Journal of NeuroscienceIt opens up new avenues to investigate how RPT6 works in the brain and how it can 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 Science in December. Farrell previously led research that identified a protein that could lead to better medical treatment for women with PTSD.

Gene expression is critical to memory formation. It helps build the neural networks needed to create and consolidate memories. Researchers do not yet understand why RPT6 has this dual function, or why it helps regulate the cells recruited to form memory.

“There has to be something else working with it to regulate gene expression,” Jarrom said. “We are now trying to understand how it works.”

Ultimately, the discovery will aid 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 to a new area of ​​understanding the complexity of the brain and how we learn and store memories,” Jarome said. “We hope this will help inform new directions for understanding how gene expression is regulated during memory. In the long term, this may lead to therapeutic targets for controlling and improving memory or treating distorted memories.”

Key findings

  • Dual function of RPT6: The RPT6 protein, found in every cell, was previously known for its role in proteasome assembly. The study showed that during memory formation, RPT6 exhibits a unique dual function by binding to DNA and regulating gene expression.
  • Implications for memory usage: Understanding the dual role of RPT6 provides insights into the complex processes of memory formation. This knowledge may pave the way for therapeutic interventions aimed at improving memory or alleviating negative memories associated with conditions such as PTSD.
  • Importance for future research. The research is a critical step toward unraveling the complexity of the brain and the regulation of gene expression during memory formation. Researchers anticipate that further investigation into the mechanisms of RPT6 will inform new directions for understanding memory at the molecular level.

So memory research news

Author: Margaret Ashburn
Source: Virginia Tech
Contact: Margaret Ashburn – Virginia Tech
Image: Image credited to Neuroscience News.

Preliminary study: Closed access.
Phosphorylation of RPT6 regulates its ability to bind DNA and regulate gene expression in the hippocampus of male rats during memory formation.” by Tim Jarrom et al Journal of Neuroscience


Phosphorylation of RPT6 regulates its ability to bind DNA and regulate gene expression in the hippocampus of male rats during memory formation.

Memory formation requires the coordinated regulation of gene expression, protein synthesis, and ubiquitin-proteasome system (UPS)-mediated protein degradation. The catalytic component of the UPS, the 26S proteasome, the 20S catalytic core is surrounded by two 19S regulatory caps, and the 19S cap regulatory subunit RPT6 is extensively activated by phosphorylation of serine 120 (pRPT6-S120) in an activity-dependent manner. in proteolytic activity.

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

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

By CRISPR-dCas9-mediated artificial knockdown of an RPT6 target gene, we found that RPT6 DNA binding alone may be important for altering gene expression following learning.

Furthermore, CRISPR-dCas13-mediated conversion of S120 to glycine by RPT6 revealed that phosphorylation of RPT6 at S120 is essential for DNA binding and precise regulation of transcription during memory formation.

Together, we reveal a novel function for RPT6 phosphorylation to regulate gene transcription during memory formation.