insight - Neuroscience - # Subcellular Regulation of Non-Lethal Caspase Activation

Proximity-Based Regulation of Non-Lethal Caspase Activation in Drosophila Olfactory Receptor Neurons

Q: How do the specific interactions between executioner caspases and their proximal membrane proteins, such as Fas3G, influence the regulation of non-lethal caspase activation in different neuronal subtypes or developmental stages?

The interactions between executioner caspases, particularly Drice, and their proximal membrane proteins like Fas3G play a crucial role in the regulation of non-lethal caspase activation across various neuronal subtypes and developmental stages. These interactions establish a spatially restricted environment where caspases can be activated without triggering apoptosis. In the context of Drosophila olfactory receptor neurons (ORNs), the proximity of Drice to Fas3G allows for localized caspase activation, which is essential for modulating neuronal functions such as synaptic plasticity and behavior without causing cell death. During different developmental stages, the expression levels and isoforms of membrane proteins like Fas3 can vary, influencing the extent and nature of caspase activation. For instance, the specific splicing isoform Fas3G was shown to enhance non-lethal caspase activation by promoting the expression of the initiator caspase Dronc, which is also proximal to Fas3G. This suggests that the regulatory mechanisms of caspase activation are not only dependent on the presence of executioner caspases but also on the specific interactions with membrane proteins that can vary between neuronal subtypes. Consequently, the ability to fine-tune caspase activity through these interactions allows for a more nuanced control of neuronal function, enabling reversible modifications in response to physiological demands.

Q: What are the potential downstream substrates and cellular processes targeted by the non-lethal caspase activation facilitated by Fas3G overexpression, and how do they contribute to the modulation of neuronal function and behavior?

Non-lethal caspase activation facilitated by Fas3G overexpression likely targets a range of downstream substrates involved in critical cellular processes that modulate neuronal function and behavior. While the specific substrates of Drice in the context of non-lethal activation remain to be fully elucidated, it is known that executioner caspases can cleave various proteins involved in synaptic transmission, cytoskeletal dynamics, and signaling pathways. For example, non-lethal caspase activation may influence synaptic plasticity by modulating proteins that regulate synaptic vesicle release or receptor trafficking. This can lead to changes in synaptic strength and neuronal excitability, ultimately affecting behavior, such as olfactory attraction. Additionally, non-lethal caspase activation can participate in processes like axon pruning and dendritic remodeling, which are essential for the proper wiring of neural circuits during development and in response to environmental stimuli. Moreover, the ability of non-lethal caspase activation to suppress innate attraction behavior, as observed in the study, indicates that these processes are intricately linked to the modulation of neuronal circuits that govern behavioral responses. By selectively targeting substrates involved in these processes, non-lethal caspase activation can fine-tune neuronal activity, allowing for adaptive changes in behavior without the irreversible consequences of cell death.

Q: Could the principles of subcellularly restricted non-lethal caspase activation be applied to develop therapeutic strategies for neurological disorders or injuries, where reversible control of neuronal activity is desirable?

Yes, the principles of subcellularly restricted non-lethal caspase activation hold significant potential for developing therapeutic strategies aimed at neurological disorders or injuries where reversible control of neuronal activity is desirable. The ability to modulate neuronal function through non-lethal caspase activation offers a promising avenue for interventions that require precise control over neuronal excitability and synaptic plasticity. For instance, in conditions such as neurodegenerative diseases, where neuronal hyperactivity or excitotoxicity contributes to pathology, targeted non-lethal caspase activation could be employed to dampen excessive neuronal activity without causing cell death. This approach could help restore balance in neural circuits and improve functional outcomes. Similarly, in the context of traumatic brain injuries, the ability to selectively activate caspases in a non-lethal manner could facilitate the repair and remodeling of damaged neural circuits, promoting recovery while minimizing the risk of further neuronal loss. Furthermore, the development of specific ligands or small molecules that can enhance the interaction between executioner caspases and their proximal membrane proteins, like Fas3G, could provide a means to achieve localized and reversible modulation of caspase activity. This targeted approach would allow for the fine-tuning of neuronal responses to various stimuli, making it a valuable strategy in the treatment of a range of neurological conditions. Overall, leveraging the mechanisms of non-lethal caspase activation could pave the way for innovative therapeutic interventions that prioritize neuronal health and functional recovery.

Core Concepts

Subcellularly restricted non-lethal caspase activation is regulated by the proximity of executioner caspases to specific membrane proteins, such as the Fasciclin 3 isoform G, which promotes the expression and recruitment of the initiator caspase Dronc.

Abstract

The study investigates the regulatory mechanisms of non-lethal caspase activation in the nervous system. The authors found that the executioner caspase Drice is primarily localized to the cell membrane in the adult Drosophila brain, in proximity to a specific isoform of the cell adhesion molecule Fasciclin 3 (Fas3G).

To study the role of Fas3G in caspase regulation, the authors developed a novel reporter system called MASCaT, which enables highly sensitive detection of non-lethal caspase activity in a cell-type-specific manner. Using MASCaT, they demonstrated that overexpression of Fas3G enhances non-lethal caspase activation in olfactory receptor neurons (ORNs) without inducing cell death.

Mechanistically, Fas3G overexpression increases the expression of the initiator caspase Dronc, which also comes in close proximity to Fas3G. The Dronc-dependent non-lethal caspase activation facilitated by Fas3G overexpression suppresses innate olfactory attraction behavior in flies.

The findings suggest that the subcellular localization of executioner caspases, defined by their proximal proteins, is a key mechanism regulating non-lethal caspase activation. Modulating the proximity of caspases to specific membrane proteins provides a means to reversibly control neuronal function without inducing cell death.

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Stats

Drice is the major executioner caspase expressed in the adult Drosophila brain.
Drice is primarily localized to the cell membrane and synaptic compartments in the adult brain.
Fas3G, a specific isoform of the cell adhesion molecule Fasciclin 3, is in close proximity to the executioner caspase Drice.
Overexpression of Fas3G enhances non-lethal caspase activation in olfactory receptor neurons in a Dronc-dependent manner.
Fas3G overexpression-facilitated non-lethal caspase activation suppresses innate olfactory attraction behavior in flies.

Quotes

"Subcellularly restricted caspase activation mediated by caspase proximal proteins is one of the potential mechanisms regulating caspase activation without inducing cell death."
"The 'hotspot' for non-lethal caspase activity appears to be determined by these neighboring proteins of executioner caspases."
"Alternative splicing may not only diversify the protein itself, but also its interaction networks to regulate module-dependent activation."

Key Insights Distilled From

Executioner caspase is proximal to Fasciclin 3 which facilitates non-lethal activation in Drosophila olfactory receptor neurons

by Muramoto,M.,... at www.biorxiv.org 07-20-2023

https://www.biorxiv.org/content/10.1101/2023.07.20.549821v3

Deeper Inquiries

How do the specific interactions between executioner caspases and their proximal membrane proteins, such as Fas3G, influence the regulation of non-lethal caspase activation in different neuronal subtypes or developmental stages?

The interactions between executioner caspases, particularly Drice, and their proximal membrane proteins like Fas3G play a crucial role in the regulation of non-lethal caspase activation across various neuronal subtypes and developmental stages. These interactions establish a spatially restricted environment where caspases can be activated without triggering apoptosis. In the context of Drosophila olfactory receptor neurons (ORNs), the proximity of Drice to Fas3G allows for localized caspase activation, which is essential for modulating neuronal functions such as synaptic plasticity and behavior without causing cell death.
During different developmental stages, the expression levels and isoforms of membrane proteins like Fas3 can vary, influencing the extent and nature of caspase activation. For instance, the specific splicing isoform Fas3G was shown to enhance non-lethal caspase activation by promoting the expression of the initiator caspase Dronc, which is also proximal to Fas3G. This suggests that the regulatory mechanisms of caspase activation are not only dependent on the presence of executioner caspases but also on the specific interactions with membrane proteins that can vary between neuronal subtypes. Consequently, the ability to fine-tune caspase activity through these interactions allows for a more nuanced control of neuronal function, enabling reversible modifications in response to physiological demands.

What are the potential downstream substrates and cellular processes targeted by the non-lethal caspase activation facilitated by Fas3G overexpression, and how do they contribute to the modulation of neuronal function and behavior?

Non-lethal caspase activation facilitated by Fas3G overexpression likely targets a range of downstream substrates involved in critical cellular processes that modulate neuronal function and behavior. While the specific substrates of Drice in the context of non-lethal activation remain to be fully elucidated, it is known that executioner caspases can cleave various proteins involved in synaptic transmission, cytoskeletal dynamics, and signaling pathways.
For example, non-lethal caspase activation may influence synaptic plasticity by modulating proteins that regulate synaptic vesicle release or receptor trafficking. This can lead to changes in synaptic strength and neuronal excitability, ultimately affecting behavior, such as olfactory attraction. Additionally, non-lethal caspase activation can participate in processes like axon pruning and dendritic remodeling, which are essential for the proper wiring of neural circuits during development and in response to environmental stimuli.
Moreover, the ability of non-lethal caspase activation to suppress innate attraction behavior, as observed in the study, indicates that these processes are intricately linked to the modulation of neuronal circuits that govern behavioral responses. By selectively targeting substrates involved in these processes, non-lethal caspase activation can fine-tune neuronal activity, allowing for adaptive changes in behavior without the irreversible consequences of cell death.

Could the principles of subcellularly restricted non-lethal caspase activation be applied to develop therapeutic strategies for neurological disorders or injuries, where reversible control of neuronal activity is desirable?

Yes, the principles of subcellularly restricted non-lethal caspase activation hold significant potential for developing therapeutic strategies aimed at neurological disorders or injuries where reversible control of neuronal activity is desirable. The ability to modulate neuronal function through non-lethal caspase activation offers a promising avenue for interventions that require precise control over neuronal excitability and synaptic plasticity.
For instance, in conditions such as neurodegenerative diseases, where neuronal hyperactivity or excitotoxicity contributes to pathology, targeted non-lethal caspase activation could be employed to dampen excessive neuronal activity without causing cell death. This approach could help restore balance in neural circuits and improve functional outcomes. Similarly, in the context of traumatic brain injuries, the ability to selectively activate caspases in a non-lethal manner could facilitate the repair and remodeling of damaged neural circuits, promoting recovery while minimizing the risk of further neuronal loss.
Furthermore, the development of specific ligands or small molecules that can enhance the interaction between executioner caspases and their proximal membrane proteins, like Fas3G, could provide a means to achieve localized and reversible modulation of caspase activity. This targeted approach would allow for the fine-tuning of neuronal responses to various stimuli, making it a valuable strategy in the treatment of a range of neurological conditions. Overall, leveraging the mechanisms of non-lethal caspase activation could pave the way for innovative therapeutic interventions that prioritize neuronal health and functional recovery.