Version 1
: Received: 26 December 2018 / Approved: 28 December 2018 / Online: 28 December 2018 (05:09:28 CET)
Version 2
: Received: 20 January 2019 / Approved: 21 January 2019 / Online: 21 January 2019 (10:32:03 CET)
How to cite:
Keefe, A. Mechanisms of Aggresome Biogenesis: Ubiquitination, Transport, & Maintenance. Preprints2018, 2018120332. https://doi.org/10.20944/preprints201812.0332.v2
Keefe, A. Mechanisms of Aggresome Biogenesis: Ubiquitination, Transport, & Maintenance. Preprints 2018, 2018120332. https://doi.org/10.20944/preprints201812.0332.v2
Keefe, A. Mechanisms of Aggresome Biogenesis: Ubiquitination, Transport, & Maintenance. Preprints2018, 2018120332. https://doi.org/10.20944/preprints201812.0332.v2
APA Style
Keefe, A. (2019). Mechanisms of Aggresome Biogenesis: Ubiquitination, Transport, & Maintenance. Preprints. https://doi.org/10.20944/preprints201812.0332.v2
Chicago/Turabian Style
Keefe, A. 2019 "Mechanisms of Aggresome Biogenesis: Ubiquitination, Transport, & Maintenance" Preprints. https://doi.org/10.20944/preprints201812.0332.v2
Abstract
Neurodegenerative diseases are universally marked by the accumulation of misfolded protein. Neurons respond to these proteostatic disturbances by sequestering, and thus inactivating, toxic misfolded proteins into a perinuclear organelle called the aggresome. The aggresome can be subsequently degraded in bulk by autophagy, a process termed aggrephagy. The formation of protein aggregates has historically been considered a spontaneous and unregulated process, but emerging research has instead discovered a diverse cohort of regulatory proteins that mediate protein aggregation. Chaperones are the first proteins to respond to misfolded proteins, and do so by recognizing the aberrant exposure of hydrophobic domains. When chaperones are unable to correctly refold proteins, their substrates are transferred to ubiquitin ligating machinery to catalyze polyubiquitination. Although ubiquitin chains typically direct proteins towards proteasomes, severe proteotoxic stress can overwhelm, or even directly inhibit, proteasomes. As an alternative to proteasomal degradation, misfolded proteins are redirected towards the mitotic organizing center (MTOC) and, following retrograde transport by dynein, are packaged and sequestered within an intermediate filament (IF) cage to form the aggresome. The biogenesis of the aggresome is thus a highly regulated event, and a better understanding of the mechanisms facilitating this process will provide critical insight into neurodegenerative disease.
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
