Proteomic identification of synaptic caspase substrates.

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Synaptic pruning is vital for brain development and implicated in neurodegenerative diseases.
• Caspase-mediated pathways contribute to neuronal dysfunction and death in Alzheimer's, Parkinson's, and Huntington's diseases.
• Identifying caspase targets is key to understanding synapse elimination.

Purpose of the Study:

• To conduct the first global analysis of caspase-mediated cleavage events in mammalian brain synapses.
• To identify and catalog synapse-specific or synapse-enriched caspase targets.
• To provide insights into caspase roles in synaptic plasticity and neurodegeneration.

Main Methods:

• Utilized a gel-based proteomics approach for global analysis.
• Employed both in vitro (recombinant caspases) and in vivo (ethanol-induced apoptosis) models.
• Validated novel targets using Western blot.

Main Results:

• Identified over 70 putative caspase cleavage substrates in brain synapses.
• Confirmed 22 known caspase substrates.
• Discovered and validated novel targets, including ATP6V1B2 and NSF.

Conclusions:

• This work presents the first comprehensive proteome-wide screen for caspase targets in neuronal synapses.
• Findings advance understanding of caspases in synaptic plasticity and loss.
• Identified targets may serve as biomarkers for synapse loss in human diseases.