PT  - JOURNAL ARTICLE
AU  - Sven Truckenbrodt
AU  - Abhiyan Viplav
AU  - Sebastian Jähne
AU  - Angela Vogts
AU  - Annette Denker
AU  - Hanna Wildhagen
AU  - Eugenio F. Fornasiero
AU  - Silvio O. Rizzoli
TI  - Ageing synaptic vesicles are inactivated by contamination with SNAP25
AID  - 10.1101/172239
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 172239
4099  - http://biorxiv.org/content/early/2017/08/03/172239.short
4100  - http://biorxiv.org/content/early/2017/08/03/172239.full
AB  - Old organelles can become a hazard to cellular function, by accumulating molecular damage. Mechanisms that identify aged organelles, and prevent them from participating in cellular reactions, are therefore necessary. We describe here one such mechanism, which acts as a timer that inactivates aged synaptic vesicles. Using cultured hippocampal neurons, we found that newly synthesized vesicle proteins are incorporated in the active (recycling) pool, and are preferentially employed in neurotransmitter release. They remain in use for up to ~24 hours, during which they recycle ~200 times, on average. Over this period the vesicles of the active pool become contaminated with the plasma membrane protein SNAP25, which inhibits the vesicle-associated chaperone CSPα. This renders these used vesicles less competent to release than newly synthesized ones that lack SNAP25. The old and contaminated vesicles are eventually targeted for degradation, possibly through the direct involvement of SNAP25. This timer mechanism can be circumvented by over-expressing CSPα, which, however, leads to less efficient recycling, and to neurite degeneration.