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

Georg Meisl; Catherine K. Xu; Jonathan D. Taylor; Thomas C.T. Michaels; Aviad Levin; Daniel Otzen; David Klenerman; Steve Matthews; Sara Linse; Maria Andreasen; Tuomas P.J. Knowles

doi:10.1126/sciadv.abn6831

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

Georg Meisl, Catherine K. Xu, Jonathan D. Taylor, Thomas C.T. Michaels, Aviad Levin, Daniel Otzen, David Klenerman, Steve Matthews, Sara Linse^*, Maria Andreasen^*, Tuomas P.J. Knowles^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

30 Citationer (Scopus)

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 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.

Originalsprog	Engelsk
Artikelnummer	eabn6831
Tidsskrift	Science Advances
Vol/bind	8
Nummer	32
ISSN	2375-2548
DOI	https://doi.org/10.1126/sciadv.abn6831
Status	Udgivet - aug. 2022

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title = "Uncovering the universality of self-replication in protein aggregation and its link to disease",

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 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.",

author = "Georg Meisl and Xu, {Catherine K.} and Taylor, {Jonathan D.} and Michaels, {Thomas C.T.} and Aviad Levin and Daniel Otzen and David Klenerman and Steve Matthews and Sara Linse and Maria Andreasen and Knowles, {Tuomas P.J.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2022 The Authors, some rights reserved.",

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doi = "10.1126/sciadv.abn6831",

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AU - Meisl, Georg

AU - Xu, Catherine K.

AU - Taylor, Jonathan D.

AU - Michaels, Thomas C.T.

AU - Levin, Aviad

AU - Otzen, Daniel

AU - Klenerman, David

AU - Matthews, Steve

AU - Linse, Sara

AU - Andreasen, Maria

AU - Knowles, Tuomas P.J.

PY - 2022/8

Y1 - 2022/8

N2 - 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.

AB - 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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VL - 8

JO - Science Advances

JF - Science Advances

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

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