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Activity-dependent dynamics and sequestration of proteasomes in dendritic spines


The regulated degradation of proteins by the ubiquitin proteasome pathway is emerging as an important modulator of synaptic function and plasticity1,2,3,4,5,6,7,8,9,10,11,12,13,14,15. The proteasome is a large, multi-subunit cellular machine that recognizes, unfolds and degrades target polyubiquitinated proteins. Here we report NMDA (N-methyl-d-aspartate) receptor-dependent redistribution of proteasomes from dendritic shafts to synaptic spines upon synaptic stimulation, providing a mechanism for local protein degradation. Using a proteasome-activity reporter and local perfusion, we show that synaptic stimulation regulates proteasome activity locally in the dendrites. We used restricted photobleaching of individual spines and dendritic shafts to reveal the dynamics that underlie proteasome sequestration, and show that activity modestly enhances the entry rate of proteasomes into spines while dramatically reducing their exit rate. Proteasome sequestration is persistent, reflecting an association with the actin-based cytoskeleton. Together, our data indicate that synaptic activity can promote the recruitment and sequestration of proteasomes to locally remodel the protein composition of synapses.

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Figure 1: A GFP-labelled proteasome subunit, Rpt1-GFP, moves into spines upon depolarization.
Figure 2: Endogenous proteasomes move into spines.
Figure 3: KCl stimulation increases proteasome activity.
Figure 4: Photobleaching of Rpt1–GFP indicates the tight association of proteasomes with spines.
Figure 5: The proteasome associates with the actin cytoskeleton.


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We thank the Kloetzel, Masucci and Kennedy laboratories for providing the Rpt1(CIM5)–GFP, UbG76V–GFP and mRFP clones, respectively. We also thank members of the Schuman laboratory, especially C.-Y. Tai and S. Kim, and former member G. Patrick for discussions. E.M.S. is an Investigator of the Howard Hughes Medical Institute.

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Correspondence to Erin M. Schuman.

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Supplementary Notes

This file contains Supplementary Figures 1–6 and Supplementary Legends 1–6, Supplementary Methods, Supplementary Notes (additional references pertaining to supplementary methods) and Supplementary Table 1. (PDF 7302 kb)

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Bingol, B., Schuman, E. Activity-dependent dynamics and sequestration of proteasomes in dendritic spines. Nature 441, 1144–1148 (2006).

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