Seed-competent tau monomer initiates pathology in a tauopathy mouse model
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved..
Tau aggregation into ordered assemblies causes neurodegenerative tauopathies. We previously reported that tau monomer exists in either inert (Mi) or seed-competent (Ms) conformational ensembles and that Ms encodes strains, that is, unique, self-replicating, biologically active assemblies. It is unknown if disease begins with Ms formation followed by fibril assembly or if Ms derives from fibrils and is therefore an epiphenomenon. Here, we studied a tauopathy mouse model (PS19) that expresses full-length mutant human (1N4R) tau (P301S). Insoluble tau seeding activity appeared at 2 months of age and insoluble tau protein assemblies by immunoblot at 3 months. Tau monomer from mice aged 1 to 6 weeks, purified using size-exclusion chromatography, contained soluble seeding activity at 4 weeks, before insoluble material or larger assemblies were observed, with assemblies ranging from n = 1 to 3 tau units. By 5 to 6 weeks, large soluble assemblies had formed. This indicated that the first detectable pathological forms of tau were in fact Ms. We next examined posttranslational modifications of tau monomer from 1 to 6 weeks. We detected no phosphorylation unique to Ms in PS19 or human Alzheimer's disease brains. We conclude that tauopathy begins with formation of the Ms monomer, whose activity is phosphorylation independent. Ms then self assembles to form oligomers before it forms insoluble fibrils. The conversion of tau monomer from Mi to Ms thus constitutes the first detectable step in the initiation of tauopathy in this mouse model, with obvious implications for the origins of tauopathy in humans.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2022 |
---|---|
Erschienen: |
2022 |
Enthalten in: |
Zur Gesamtaufnahme - volume:298 |
---|---|
Enthalten in: |
The Journal of biological chemistry - 298(2022), 8 vom: 15. Aug., Seite 102163 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Mirbaha, Hilda [VerfasserIn] |
---|
Links: |
---|
Themen: |
Journal Article |
---|
Anmerkungen: |
Date Completed 08.09.2022 Date Revised 17.10.2022 published: Print-Electronic Citation Status MEDLINE |
---|
doi: |
10.1016/j.jbc.2022.102163 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM342712632 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM342712632 | ||
003 | DE-627 | ||
005 | 20231226014744.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231226s2022 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1016/j.jbc.2022.102163 |2 doi | |
028 | 5 | 2 | |a pubmed24n1142.xml |
035 | |a (DE-627)NLM342712632 | ||
035 | |a (NLM)35750209 | ||
035 | |a (PII)S0021-9258(22)00605-6 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Mirbaha, Hilda |e verfasserin |4 aut | |
245 | 1 | 0 | |a Seed-competent tau monomer initiates pathology in a tauopathy mouse model |
264 | 1 | |c 2022 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 08.09.2022 | ||
500 | |a Date Revised 17.10.2022 | ||
500 | |a published: Print-Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved. | ||
520 | |a Tau aggregation into ordered assemblies causes neurodegenerative tauopathies. We previously reported that tau monomer exists in either inert (Mi) or seed-competent (Ms) conformational ensembles and that Ms encodes strains, that is, unique, self-replicating, biologically active assemblies. It is unknown if disease begins with Ms formation followed by fibril assembly or if Ms derives from fibrils and is therefore an epiphenomenon. Here, we studied a tauopathy mouse model (PS19) that expresses full-length mutant human (1N4R) tau (P301S). Insoluble tau seeding activity appeared at 2 months of age and insoluble tau protein assemblies by immunoblot at 3 months. Tau monomer from mice aged 1 to 6 weeks, purified using size-exclusion chromatography, contained soluble seeding activity at 4 weeks, before insoluble material or larger assemblies were observed, with assemblies ranging from n = 1 to 3 tau units. By 5 to 6 weeks, large soluble assemblies had formed. This indicated that the first detectable pathological forms of tau were in fact Ms. We next examined posttranslational modifications of tau monomer from 1 to 6 weeks. We detected no phosphorylation unique to Ms in PS19 or human Alzheimer's disease brains. We conclude that tauopathy begins with formation of the Ms monomer, whose activity is phosphorylation independent. Ms then self assembles to form oligomers before it forms insoluble fibrils. The conversion of tau monomer from Mi to Ms thus constitutes the first detectable step in the initiation of tauopathy in this mouse model, with obvious implications for the origins of tauopathy in humans | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, N.I.H., Extramural | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 4 | |a pathology | |
650 | 4 | |a prion | |
650 | 4 | |a seed-competent monomer | |
650 | 4 | |a size-exclusion chromatography | |
650 | 4 | |a tauopathy | |
650 | 4 | |a tauopathy mouse model | |
650 | 7 | |a tau Proteins |2 NLM | |
700 | 1 | |a Chen, Dailu |e verfasserin |4 aut | |
700 | 1 | |a Mullapudi, Vishruth |e verfasserin |4 aut | |
700 | 1 | |a Terpack, Sandi Jo |e verfasserin |4 aut | |
700 | 1 | |a White, Charles L |c 3rd |e verfasserin |4 aut | |
700 | 1 | |a Joachimiak, Lukasz A |e verfasserin |4 aut | |
700 | 1 | |a Diamond, Marc I |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t The Journal of biological chemistry |d 1945 |g 298(2022), 8 vom: 15. Aug., Seite 102163 |w (DE-627)NLM000004995 |x 1083-351X |7 nnns |
773 | 1 | 8 | |g volume:298 |g year:2022 |g number:8 |g day:15 |g month:08 |g pages:102163 |
856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.jbc.2022.102163 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 298 |j 2022 |e 8 |b 15 |c 08 |h 102163 |