Tryptophan residue 32 in human Cu-Zn superoxide dismutase modulates prion-like propagation and strain selection.

Mutations in Cu/Zn superoxide dismutase 1 (SOD1) associated with familial amyotrophic lateral sclerosis cause the protein to aggregate via a prion-like process in which soluble molecules are recruited to aggregates by conformational templating. These misfolded SOD1 proteins can propagate aggregation...

Full description

Bibliographic Details
Main Authors: Anthony Crown, Luke McAlary, Eric Fagerli, Hilda Brown, Justin J Yerbury, Ahmad Galaleldeen, Neil R Cashman, David R Borchelt, Jacob I Ayers
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2020-01-01
Series:PLoS ONE
Online Access:https://doi.org/10.1371/journal.pone.0227655
_version_ 1818591135355895808
author Anthony Crown
Luke McAlary
Eric Fagerli
Hilda Brown
Justin J Yerbury
Ahmad Galaleldeen
Neil R Cashman
David R Borchelt
Jacob I Ayers
author_facet Anthony Crown
Luke McAlary
Eric Fagerli
Hilda Brown
Justin J Yerbury
Ahmad Galaleldeen
Neil R Cashman
David R Borchelt
Jacob I Ayers
author_sort Anthony Crown
collection DOAJ
description Mutations in Cu/Zn superoxide dismutase 1 (SOD1) associated with familial amyotrophic lateral sclerosis cause the protein to aggregate via a prion-like process in which soluble molecules are recruited to aggregates by conformational templating. These misfolded SOD1 proteins can propagate aggregation-inducing conformations across cellular membranes. Prior studies demonstrated that mutation of a Trp (W) residue at position 32 to Ser (S) suppresses the propagation of misfolded conformations between cells, whereas other studies have shown that mutation of Trp 32 to Phe (F), or Cys 111 to Ser, can act in cis to attenuate aggregation of mutant SOD1. By expressing mutant SOD1 fused with yellow fluorescent protein (YFP), we compared the relative ability of these mutations to modulate the formation of inclusions by ALS-mutant SOD1 (G93A and G85R). Only mutation of Trp 32 to Ser persistently reduced the formation of the amorphous inclusions that form in these cells, consistent with the idea that a Ser at position 32 inhibits templated propagation of aggregation prone conformations. To further test this idea, we produced aggregated fibrils of recombinant SOD1-W32S in vitro and injected them into the spinal cords of newborn mice expressing G85R-SOD1: YFP. The injected mice developed an earlier onset paralysis with a frequency similar to mice injected with WT SOD1 fibrils, generating a strain of misfolded SOD1 that produced highly fibrillar inclusion pathology. These findings suggest that the effect of Trp 32 in modulating the propagation of misfolded SOD1 conformations may be dependent upon the "strain" of the conformer that is propagating.
first_indexed 2024-12-16T10:07:37Z
format Article
id doaj.art-2780c523d04745fcb6fa967d68601d3b
institution Directory Open Access Journal
issn 1932-6203
language English
last_indexed 2024-12-16T10:07:37Z
publishDate 2020-01-01
publisher Public Library of Science (PLoS)
record_format Article
series PLoS ONE
spelling doaj.art-2780c523d04745fcb6fa967d68601d3b2022-12-21T22:35:38ZengPublic Library of Science (PLoS)PLoS ONE1932-62032020-01-01151e022765510.1371/journal.pone.0227655Tryptophan residue 32 in human Cu-Zn superoxide dismutase modulates prion-like propagation and strain selection.Anthony CrownLuke McAlaryEric FagerliHilda BrownJustin J YerburyAhmad GalaleldeenNeil R CashmanDavid R BorcheltJacob I AyersMutations in Cu/Zn superoxide dismutase 1 (SOD1) associated with familial amyotrophic lateral sclerosis cause the protein to aggregate via a prion-like process in which soluble molecules are recruited to aggregates by conformational templating. These misfolded SOD1 proteins can propagate aggregation-inducing conformations across cellular membranes. Prior studies demonstrated that mutation of a Trp (W) residue at position 32 to Ser (S) suppresses the propagation of misfolded conformations between cells, whereas other studies have shown that mutation of Trp 32 to Phe (F), or Cys 111 to Ser, can act in cis to attenuate aggregation of mutant SOD1. By expressing mutant SOD1 fused with yellow fluorescent protein (YFP), we compared the relative ability of these mutations to modulate the formation of inclusions by ALS-mutant SOD1 (G93A and G85R). Only mutation of Trp 32 to Ser persistently reduced the formation of the amorphous inclusions that form in these cells, consistent with the idea that a Ser at position 32 inhibits templated propagation of aggregation prone conformations. To further test this idea, we produced aggregated fibrils of recombinant SOD1-W32S in vitro and injected them into the spinal cords of newborn mice expressing G85R-SOD1: YFP. The injected mice developed an earlier onset paralysis with a frequency similar to mice injected with WT SOD1 fibrils, generating a strain of misfolded SOD1 that produced highly fibrillar inclusion pathology. These findings suggest that the effect of Trp 32 in modulating the propagation of misfolded SOD1 conformations may be dependent upon the "strain" of the conformer that is propagating.https://doi.org/10.1371/journal.pone.0227655
spellingShingle Anthony Crown
Luke McAlary
Eric Fagerli
Hilda Brown
Justin J Yerbury
Ahmad Galaleldeen
Neil R Cashman
David R Borchelt
Jacob I Ayers
Tryptophan residue 32 in human Cu-Zn superoxide dismutase modulates prion-like propagation and strain selection.
PLoS ONE
title Tryptophan residue 32 in human Cu-Zn superoxide dismutase modulates prion-like propagation and strain selection.
title_full Tryptophan residue 32 in human Cu-Zn superoxide dismutase modulates prion-like propagation and strain selection.
title_fullStr Tryptophan residue 32 in human Cu-Zn superoxide dismutase modulates prion-like propagation and strain selection.
title_full_unstemmed Tryptophan residue 32 in human Cu-Zn superoxide dismutase modulates prion-like propagation and strain selection.
title_short Tryptophan residue 32 in human Cu-Zn superoxide dismutase modulates prion-like propagation and strain selection.
title_sort tryptophan residue 32 in human cu zn superoxide dismutase modulates prion like propagation and strain selection
url https://doi.org/10.1371/journal.pone.0227655
work_keys_str_mv AT anthonycrown tryptophanresidue32inhumancuznsuperoxidedismutasemodulatesprionlikepropagationandstrainselection
AT lukemcalary tryptophanresidue32inhumancuznsuperoxidedismutasemodulatesprionlikepropagationandstrainselection
AT ericfagerli tryptophanresidue32inhumancuznsuperoxidedismutasemodulatesprionlikepropagationandstrainselection
AT hildabrown tryptophanresidue32inhumancuznsuperoxidedismutasemodulatesprionlikepropagationandstrainselection
AT justinjyerbury tryptophanresidue32inhumancuznsuperoxidedismutasemodulatesprionlikepropagationandstrainselection
AT ahmadgalaleldeen tryptophanresidue32inhumancuznsuperoxidedismutasemodulatesprionlikepropagationandstrainselection
AT neilrcashman tryptophanresidue32inhumancuznsuperoxidedismutasemodulatesprionlikepropagationandstrainselection
AT davidrborchelt tryptophanresidue32inhumancuznsuperoxidedismutasemodulatesprionlikepropagationandstrainselection
AT jacobiayers tryptophanresidue32inhumancuznsuperoxidedismutasemodulatesprionlikepropagationandstrainselection