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Uncovering the universality of self-replication in protein aggregation and its link to disease

Meisl, Georg ; Xu, Catherine K. ; Taylor, Jonathan D. ; Michaels, Thomas C. T. ; Levin, Aviad ; Otzen, Daniel ; Klenerman, David ; Matthews, Steve ; Linse, Sara LU and Andreasen, Maria , et al. (2022) In Science Advances 8(32).
Abstract

Fibrillar protein aggregates are a hallmark of a range of human disorders, from prion diseases to dementias, but are also encountered in several functional contexts. Yet, the fundamental links between protein assembly mechanisms and their functional or pathological roles have remained elusive. Here, we analyze the aggregation kinetics of a large set of proteins that self-assemble by a nucleated-growth mechanism, from those associated with disease, over those whose aggregates fulfill functional roles in biology, to those that aggregate only under artificial conditions. We find that, essentially, all such systems, regardless of their biological role, are capable of self-replication. However, for aggregates that have evolved to fulfill a... (More)

Fibrillar protein aggregates are a hallmark of a range of human disorders, from prion diseases to dementias, but are also encountered in several functional contexts. Yet, the fundamental links between protein assembly mechanisms and their functional or pathological roles have remained elusive. Here, we analyze the aggregation kinetics of a large set of proteins that self-assemble by a nucleated-growth mechanism, from those associated with disease, over those whose aggregates fulfill functional roles in biology, to those that aggregate only under artificial conditions. We find that, essentially, all such systems, regardless of their biological role, are capable of self-replication. However, for aggregates that have evolved to fulfill a structural role, the rate of self-replication is too low to be significant on the biologically relevant time scale. By contrast, all disease-related proteins are able to self-replicate quickly compared to the time scale of the associated disease. Our findings establish the ubiquity of self-replication and point to its potential importance across aggregation-related disorders.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Advances
volume
8
issue
32
article number
eabn6831
pages
10 pages
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • scopus:85135944758
  • pmid:35960802
ISSN
2375-2548
DOI
10.1126/sciadv.abn6831
language
English
LU publication?
yes
id
32ba83ab-de5e-4a82-bc11-7c02b15c1ec1
date added to LUP
2022-10-28 15:08:18
date last changed
2024-06-15 00:53:15
@article{32ba83ab-de5e-4a82-bc11-7c02b15c1ec1,
  abstract     = {{<p>Fibrillar protein aggregates are a hallmark of a range of human disorders, from prion diseases to dementias, but are also encountered in several functional contexts. Yet, the fundamental links between protein assembly mechanisms and their functional or pathological roles have remained elusive. Here, we analyze the aggregation kinetics of a large set of proteins that self-assemble by a nucleated-growth mechanism, from those associated with disease, over those whose aggregates fulfill functional roles in biology, to those that aggregate only under artificial conditions. We find that, essentially, all such systems, regardless of their biological role, are capable of self-replication. However, for aggregates that have evolved to fulfill a structural role, the rate of self-replication is too low to be significant on the biologically relevant time scale. By contrast, all disease-related proteins are able to self-replicate quickly compared to the time scale of the associated disease. Our findings establish the ubiquity of self-replication and point to its potential importance across aggregation-related disorders.</p>}},
  author       = {{Meisl, Georg and Xu, Catherine K. and Taylor, Jonathan D. and Michaels, Thomas C. T. and Levin, Aviad and Otzen, Daniel and Klenerman, David and Matthews, Steve and Linse, Sara and Andreasen, Maria and Knowles, Tuomas P. J.}},
  issn         = {{2375-2548}},
  language     = {{eng}},
  number       = {{32}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science Advances}},
  title        = {{Uncovering the universality of self-replication in protein aggregation and its link to disease}},
  url          = {{http://dx.doi.org/10.1126/sciadv.abn6831}},
  doi          = {{10.1126/sciadv.abn6831}},
  volume       = {{8}},
  year         = {{2022}},
}