April 21, 2024

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Unlocking the secrets of the synapse: the role of the FAM81A protein

Unlocking the secrets of the synapse: the role of the FAM81A protein

summary: The researchers identified an important protein, FAM81A, that plays a pivotal role in the formation of postsynaptic protein aggregates, which is essential for synaptic function in the brain. By analyzing 35 previous studies, the team discovered the persistent presence of FAM81A in the postsynaptic density, a complex protein structure vital for transmitting nerve signals.

The interaction of this protein with major postsynaptic proteins and its participation in liquid-liquid phase separation underscores its importance in maintaining synaptic activity. The results not only contribute to our understanding of synaptic mechanisms, but also open new avenues for exploring the evolution of cognitive functions in higher vertebrates and potential implications for neuropsychiatric conditions.

Key facts:

  1. FAM81A's critical role in synapses: FAM81A interacts with key postsynaptic proteins, regulates their assembly and affects neuronal function.
  2. First comprehensive description: This study provides the first complete characterization of FAM81A, highlighting its involvement in synaptic density formation and activity.
  3. Evolutionary insights: The evolutionary divergence between FAM81A and its homologs across species suggests its unique role in the cognitive functions of higher vertebrate brains.

source: Kobe University

A protein that appears in postsynaptic protein clumps was found to be crucial in their formation. The Kobe University discovery identifies a new key player for synaptic function and sheds the first light on its hitherto uncharacterized role and cellular evolution.

What happens at the synapse, the connection between two nerve cells, is a key factor in brain function. The signal is transmitted from presynaptic neurons to postsynaptic neurons by proteins and their imbalance can lead to neuropsychiatric conditions such as major depression, autism, or alcohol dependence.

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Humans have two related copies of the gene, FAM81A and FAM81B. Credit: Neuroscience News

However, due to the great diversity of proteins found at this junction, many of them have not yet been studied, and it is often not clear whether previously found proteins actually belong there or are just impurities resulting from the analysis process.

A particularly conspicuous structure located directly beneath the postsynaptic membrane is what is called the “postsynaptic density,” which is a clumping of perhaps thousands of different proteins.

To shed some light on postsynaptic density, Kobe University neurophysiologist Takumi Toru and his team first compared 35 datasets from previous studies on this phenomenon to see which uncharacterized proteins consistently appeared.

“We created an analytical pipeline to standardize and align protein structures in different datasets,” explains Kaizuka Takeshi, first author of the paper. “This led to the identification of a poorly characterized synaptic protein that was detected in more than 20 of these datasets.”

This suggested that the protein, labeled FAM81A, might be relevant to the function of the entire structure, so the team analyzed its interactions with other proteins, its distribution in and around neurons and its effect on the shape and function of neurons. Its mechanism of action and development. In short, they have given this protein a complete preliminary description.

Takumi summarizes their findings now published in the journal PLoS Biology“The important finding is that FAM81A interacts with at least three key postsynaptic proteins and regulates their condensation. This suggests that FAM81A is a key regulatory factor in postsynaptic density.

The group can confirm that FAM81A facilitates the condensation of key proteins in a membrane-free organelle through liquid-liquid phase separation, a process in which interacting molecules strongly exclude elements of the surrounding medium, and that the absence of the protein results in a significant reduction in the protein level. Decreased activity in cultured neurons.

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Humans have two related copies of the gene, FAM81A And FAM81B. However, while FAM81A It is expressed in the brain, FAM81B It is expressed only in the testicles. Moreover, birds and reptiles also have two copies of the gene, but amphibians, fish and invertebrates have only one copy, and its expression is not localized to a single tissue.

“Interestingly, the evolutionary conservation of FAM81A function in the synapse appears to be limited compared to other synaptic molecules, as a fish FAM81A homolog has not been detected in the synapse. This suggests that FAM81A could be a key protein in understanding the cognitive functions of higher vertebrate brains.”

But their work was just the first step. To truly understand the role of the protein, it is necessary to study its function in the complex brain environment. Thus, the research team at Kobe University wants to create mouse models that lack the FAM81A gene and study what this means for the function of synapses and the behavior of the organism.

Financing: This research was supported by the Japan Society for the Promotion of Science (Grants JP16H06463, JP18K14830, JP22H04981, JP23H04233), the Japan Science and Technology Agency (JPMJMS2299), and the Takeda Science Foundation.

It was conducted in collaboration with researchers from the University of Edinburgh, Kyoto University and the University of Sheffield.

About genetics and neuroscience research news

author: Daniel Shines
source: Kobe University
communication: Daniel Shinz – Kobe University
picture: Image credited to Neuroscience News

Original search: Open access.
FAM81A is a postsynaptic protein that regulates the condensation of postsynaptic proteins by liquid-liquid phase separation.“By Takumi Toru et al. PLoS Biology

a summary

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FAM81A is a postsynaptic protein that regulates the condensation of postsynaptic proteins by liquid-liquid phase separation.

Proteomic analyzes of the postsynaptic density (PSD), a protein specialty found beneath the postsynaptic membrane of excitatory synapses, have identified several thousand proteins.

While proteins with predictable functions have been well studied, functionally uncharacterized proteins are often ignored. In this study, we performed a comprehensive meta-analysis of 35 PSD proteomic datasets, including a total of 5869 proteins.

Using classification methodology, we identified 97 proteins that remain insufficiently described. From this selection, we focused our detailed analysis on the top-ranking protein, FAM81A.

FAM81A interacts with PSD proteins, including PSD-95, SynGAP, and NMDA receptors, and promotes liquid-liquid phase separation of these proteins in cultured cells or in vitro. Down-regulation of FAM81A in cultured neurons results in a decrease in the size of PSD-95 puncta and the firing frequency of neurons.

Our findings indicate that FAM81A plays a critical role in facilitating the interaction and assembly of proteins within the PSD, and that its presence is important for maintaining normal synaptic function.

In addition, our methodology underscores the need to further characterize many synaptic proteins that still lack comprehensive understanding.