Lu, M;
Banetta, L;
Young, LJ;
Smith, EJ;
Bates, GP;
Zaccone, A;
Schierle, GSK;
... Kaminski, CF; + view all
(2019)
Live-cell super-resolution microscopy reveals a primary role for diffusion in polyglutamine-driven aggresome assembly.
Journal of Biological Chemistry
, 294
(1)
pp. 257-268.
10.1074/jbc.RA118.003500.
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Abstract
The mechanisms leading to self-assembly of misfolded proteins into amyloid aggregates have been studied extensively in the test tube under well-controlled conditions. However, to what extent these processes are representative of those in the cellular environment remains unclear. Using super-resolution imaging of live cells, we show here that an amyloidogenic polyglutamine-containing protein first forms small, amorphous aggregate clusters in the cytosol, chiefly by diffusion. Dynamic interactions among these clusters limited their elongation and led to structures with a branched morphology, differing from the predominantly linear fibrils observed in vitro. Some of these clusters then assembled via active transport at the microtubule-organizing center and thereby initiated the formation of perinuclear aggresomes. Although it is widely believed that aggresome formation is entirely governed by active transport along microtubules, here we demonstrate, using a combined approach of advanced imaging and mathematical modeling, that diffusion is the principal mechanism driving aggresome expansion. We found that the increasing surface area of the expanding aggresome increases the rate of accretion caused by diffusion of cytosolic aggregates and that this pathway soon dominates aggresome assembly. Our findings lead to a different view of aggresome formation than that proposed previously. We also show that aggresomes mature over time, becoming more compacted as the structure grows. The presence of large perinuclear aggregates profoundly affects the behavior and health of the cell, and our super-resolution imaging results indicate that aggresome formation and development are governed by highly dynamic processes that could be important for the design of potential therapeutic strategies.
Type: | Article |
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Title: | Live-cell super-resolution microscopy reveals a primary role for diffusion in polyglutamine-driven aggresome assembly |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1074/jbc.RA118.003500 |
Publisher version: | https://doi.org/10.1074/jbc.RA118.003500 |
Language: | English |
Additional information: | Copyright © 2019 Lu et al. Author's Choice—Final version open access under the terms of the Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0). |
Keywords: | protein aggregation, transport, molecular dynamics, molecular imaging, molecular modeling, protein misfolding, aggresome formation, amyloid protein, live cell SIM, passive transport |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
URI: | https://discovery.ucl.ac.uk/id/eprint/10067130 |
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