Bassoon Controls Presynaptic Autophagy through Atg5

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Mechanisms governing synaptic protein surveillance and clearance are poorly understood.
• Loss of presynaptic active zone proteins Piccolo and Bassoon leads to synaptic vesicle loss and compromised synaptic integrity.

Purpose of the Study:

• To investigate the mechanisms regulating synaptic protein clearance and integrity.
• To elucidate the role of presynaptic autophagy in the context of Piccolo and Bassoon loss.
• To identify the molecular players involved in the regulation of presynaptic autophagy.

Main Methods:

• Investigated synaptic vesicle (SV) destruction in boutons lacking Piccolo and Bassoon.
• Analyzed the role of poly-ubiquitination and the E3 ubiquitin ligase Siah1 in presynaptic autophagy.
• Examined the impact of gain and loss of function of Bassoon on presynaptic autophagy.
• Studied the interaction between Bassoon and Atg5 (a key autophagy regulator).
• Assessed the effect of Atg5 loss of function and a Bassoon-derived peptide on presynaptic autophagy.

Main Results:

• SVs destruction in Piccolo/Bassoon-deficient boutons correlated with induced presynaptic autophagy, dependent on poly-ubiquitination but not Siah1.
• Bassoon alone modulated presynaptic autophagy; its loss enhanced, while its gain suppressed, the process.
• Bassoon interacts with and inhibits Atg5 in heterologous cells.
• Atg5 loss of function and a Bassoon-derived peptide targeting Atg5 inhibited presynaptic autophagy.

Conclusions:

• Bassoon plays a critical role in the local regulation of presynaptic autophagy.
• Bassoon directly inhibits autophagy induction by interacting with Atg5.
• These findings provide novel insights into the molecular mechanisms governing presynaptic autophagy and synaptic homeostasis.