näkemys - Molecular Biology - # Synaptic Protein Turnover and Supercomplex Maintenance

Sequential Replacement of Synaptic Scaffold Proteins Maintains the Stability of Molecular Supercomplexes in the Brain

Q: How might the differential turnover of subunits within synaptic supercomplexes contribute to the encoding and storage of specific memories?

The differential turnover of subunits within synaptic supercomplexes can play a crucial role in the encoding and storage of specific memories. By allowing for the sequential replacement of individual subunits, these supercomplexes can adapt and incorporate new information while retaining the core structure necessary for memory maintenance. This process ensures that memories can be updated and modified over time without compromising the overall stability of the synaptic architecture. Specifically, the turnover of subunits within supercomplexes can facilitate the incorporation of new synaptic proteins or modifications that are essential for memory formation. For example, the replacement of old subunits with new ones may allow for the integration of updated information or the removal of outdated synaptic connections. This dynamic process of subunit turnover ensures that the supercomplexes remain flexible and responsive to changing synaptic demands, thereby enabling the encoding and storage of specific memories. Furthermore, the differential turnover of subunits within synaptic supercomplexes may contribute to the consolidation of long-term memories. By gradually replacing individual subunits over extended periods of time, these supercomplexes can maintain the stability of memory-related synaptic structures while also allowing for the gradual integration of new information. This process of continuous subunit replacement ensures that memories are retained and reinforced over time, leading to the long-term storage of specific cognitive information.

Q: What other types of synaptic protein complexes or supercomplexes might undergo similar sequential subunit replacement, and how might this process relate to their functional roles?

In addition to PSD95-containing supercomplexes, other synaptic protein complexes or supercomplexes may also undergo similar sequential subunit replacement. For example, complexes involving ionotropic glutamate receptors such as NMDA and AMPA receptors, as well as other scaffolding proteins like Shank and Homer, are likely candidates for this process. These complexes are essential for synaptic transmission and plasticity, making them key players in memory formation and storage. The process of sequential subunit replacement in these complexes is crucial for their functional roles in synaptic plasticity and memory. By continuously updating and renewing the subunits within these complexes, the synapses can adapt to changing environmental stimuli and encode new information effectively. This dynamic process ensures that the synaptic protein complexes remain responsive to synaptic activity and can modulate their function based on the demands of memory formation and storage. Furthermore, the sequential subunit replacement in these complexes may also contribute to the regulation of synaptic strength and stability. By incorporating new subunits and removing old ones, these complexes can fine-tune their interactions with other synaptic proteins and signaling molecules, thereby modulating synaptic efficacy and plasticity. This process of subunit turnover is essential for maintaining the balance between synaptic stability and flexibility, ultimately supporting the functional roles of these complexes in memory processes.

Q: Could disruptions to the mechanisms maintaining synaptic supercomplex stability contribute to the pathogenesis of neurodegenerative or neuropsychiatric disorders?

Disruptions to the mechanisms maintaining synaptic supercomplex stability could indeed contribute to the pathogenesis of neurodegenerative or neuropsychiatric disorders. Synaptic dysfunction is a common feature of many neurological and psychiatric conditions, and alterations in the stability and composition of synaptic protein complexes have been implicated in the pathophysiology of these disorders. For instance, abnormalities in the turnover of subunits within synaptic supercomplexes could lead to synaptic instability, impaired synaptic plasticity, and altered neuronal communication. These disruptions may result in cognitive deficits, memory impairments, and behavioral abnormalities characteristic of neurodegenerative and neuropsychiatric disorders. Additionally, changes in the composition or organization of synaptic protein complexes could impact the efficiency of neurotransmission, synaptic signaling, and synaptic connectivity, further contributing to disease pathology. Moreover, disruptions in the turnover of subunits within synaptic supercomplexes may also affect the maintenance of long-term memories and the formation of new synaptic connections. Dysregulation of these processes could lead to synaptic degeneration, synaptic loss, and ultimately neuronal dysfunction, which are common features of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. In neuropsychiatric disorders like schizophrenia and autism spectrum disorders, alterations in synaptic protein complexes and supercomplexes could disrupt synaptic homeostasis and contribute to the cognitive and behavioral symptoms associated with these conditions.

Keskeiset käsitteet

Synaptic scaffold proteins, such as PSD95, are organized into molecular supercomplexes that are maintained by the sequential replacement of individual subunits over time, a process linked to the protein's lifetime in different brain regions.

Tiivistelmä

The study investigates the organization and turnover of synaptic proteins, particularly the abundant scaffolding protein PSD95, within molecular supercomplexes in the mouse brain. Using single-molecule detection and super-resolution microscopy techniques, the authors make several key findings:

PSD95 is organized into supercomplexes, with the majority containing two copies of PSD95. The distance between the PSD95 molecules within these dimeric supercomplexes is 12.7 nm on average.
By tracking the fate of PSD95 subunits in vivo, the authors show that individual PSD95 proteins are sequentially replaced over days and weeks within the supercomplexes.
The rate of PSD95 subunit replacement is slowest in the cortex, where PSD95 protein lifetime is longest. This suggests a link between protein turnover and the maintenance of synaptic supercomplexes.
Comparison of synaptic and total brain PSD95 supercomplexes reveals a higher proportion of "mixed" supercomplexes containing both old and new PSD95 in the synaptic fraction, indicating that synapses preferentially retain some old subunits.

The authors propose that the sequential replacement of subunits within synaptic supercomplexes provides a mechanism for maintaining the stability of the postsynaptic density and synaptic function, even as the individual proteins are turned over. This process may be particularly important for the long-term storage of memories in cortical synapses.

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biorxiv.org

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The study reports the following key metrics:

63% of PSD95-containing supercomplexes contained 1 PSD95 protein, 24% contained 2 PSD95 proteins, and 13% contained more than 2 PSD95 proteins.
The average distance between PSD95 molecules in dimeric supercomplexes was 12.7 nm.
At 7 days after in vivo labeling, 56% of PSD95 supercomplexes contained only old (SiR-Halo labeled) PSD95, 32% contained only new (AF488-Halo labeled) PSD95, and 12% contained a mix of old and new PSD95.
The cortex had the highest percentage of mixed supercomplexes (19%) compared to other brain regions.

Lainaukset

"Our findings reveal that protein supercomplexes within the postsynaptic density can be maintained by gradual replacement of individual subunits providing a mechanism for stable maintenance of their organization."
"We extend Crick's model by suggesting that synapses with slow subunit replacement of protein supercomplexes and long protein lifetimes are specialized for long-term memory storage and that these synapses are highly enriched in superficial layers of the cortex where long-term memories are stored."

Tärkeimmät oivallukset

Sequential replacement of PSD95 subunits in postsynaptic supercomplexes is slowest in the cortex

by Morris,K., B... klo www.biorxiv.org 07-13-2023

https://www.biorxiv.org/content/10.1101/2023.07.13.548866v2

Syvällisempiä Kysymyksiä

How might the differential turnover of subunits within synaptic supercomplexes contribute to the encoding and storage of specific memories?

The differential turnover of subunits within synaptic supercomplexes can play a crucial role in the encoding and storage of specific memories. By allowing for the sequential replacement of individual subunits, these supercomplexes can adapt and incorporate new information while retaining the core structure necessary for memory maintenance. This process ensures that memories can be updated and modified over time without compromising the overall stability of the synaptic architecture.
Specifically, the turnover of subunits within supercomplexes can facilitate the incorporation of new synaptic proteins or modifications that are essential for memory formation. For example, the replacement of old subunits with new ones may allow for the integration of updated information or the removal of outdated synaptic connections. This dynamic process of subunit turnover ensures that the supercomplexes remain flexible and responsive to changing synaptic demands, thereby enabling the encoding and storage of specific memories.
Furthermore, the differential turnover of subunits within synaptic supercomplexes may contribute to the consolidation of long-term memories. By gradually replacing individual subunits over extended periods of time, these supercomplexes can maintain the stability of memory-related synaptic structures while also allowing for the gradual integration of new information. This process of continuous subunit replacement ensures that memories are retained and reinforced over time, leading to the long-term storage of specific cognitive information.

What other types of synaptic protein complexes or supercomplexes might undergo similar sequential subunit replacement, and how might this process relate to their functional roles?

In addition to PSD95-containing supercomplexes, other synaptic protein complexes or supercomplexes may also undergo similar sequential subunit replacement. For example, complexes involving ionotropic glutamate receptors such as NMDA and AMPA receptors, as well as other scaffolding proteins like Shank and Homer, are likely candidates for this process. These complexes are essential for synaptic transmission and plasticity, making them key players in memory formation and storage.
The process of sequential subunit replacement in these complexes is crucial for their functional roles in synaptic plasticity and memory. By continuously updating and renewing the subunits within these complexes, the synapses can adapt to changing environmental stimuli and encode new information effectively. This dynamic process ensures that the synaptic protein complexes remain responsive to synaptic activity and can modulate their function based on the demands of memory formation and storage.
Furthermore, the sequential subunit replacement in these complexes may also contribute to the regulation of synaptic strength and stability. By incorporating new subunits and removing old ones, these complexes can fine-tune their interactions with other synaptic proteins and signaling molecules, thereby modulating synaptic efficacy and plasticity. This process of subunit turnover is essential for maintaining the balance between synaptic stability and flexibility, ultimately supporting the functional roles of these complexes in memory processes.

Could disruptions to the mechanisms maintaining synaptic supercomplex stability contribute to the pathogenesis of neurodegenerative or neuropsychiatric disorders?

Disruptions to the mechanisms maintaining synaptic supercomplex stability could indeed contribute to the pathogenesis of neurodegenerative or neuropsychiatric disorders. Synaptic dysfunction is a common feature of many neurological and psychiatric conditions, and alterations in the stability and composition of synaptic protein complexes have been implicated in the pathophysiology of these disorders.
For instance, abnormalities in the turnover of subunits within synaptic supercomplexes could lead to synaptic instability, impaired synaptic plasticity, and altered neuronal communication. These disruptions may result in cognitive deficits, memory impairments, and behavioral abnormalities characteristic of neurodegenerative and neuropsychiatric disorders. Additionally, changes in the composition or organization of synaptic protein complexes could impact the efficiency of neurotransmission, synaptic signaling, and synaptic connectivity, further contributing to disease pathology.
Moreover, disruptions in the turnover of subunits within synaptic supercomplexes may also affect the maintenance of long-term memories and the formation of new synaptic connections. Dysregulation of these processes could lead to synaptic degeneration, synaptic loss, and ultimately neuronal dysfunction, which are common features of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. In neuropsychiatric disorders like schizophrenia and autism spectrum disorders, alterations in synaptic protein complexes and supercomplexes could disrupt synaptic homeostasis and contribute to the cognitive and behavioral symptoms associated with these conditions.