Cargando…
Protein citrullination marks myelin protein aggregation and disease progression in mouse ALS models
Increased protein citrullination (PC) and dysregulated protein arginine deiminase (PAD) activity have been observed in several neurodegenerative diseases. PC is a posttranslational modification catalyzed by the PADs. PC converts peptidyl-arginine to peptidyl-citrulline, thereby reducing the positive...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9458309/ https://www.ncbi.nlm.nih.gov/pubmed/36076282 http://dx.doi.org/10.1186/s40478-022-01433-5 |
_version_ | 1784786265646825472 |
---|---|
author | Yusuf, Issa O. Qiao, Tao Parsi, Sepideh Tilvawala, Ronak Thompson, Paul R. Xu, Zuoshang |
author_facet | Yusuf, Issa O. Qiao, Tao Parsi, Sepideh Tilvawala, Ronak Thompson, Paul R. Xu, Zuoshang |
author_sort | Yusuf, Issa O. |
collection | PubMed |
description | Increased protein citrullination (PC) and dysregulated protein arginine deiminase (PAD) activity have been observed in several neurodegenerative diseases. PC is a posttranslational modification catalyzed by the PADs. PC converts peptidyl-arginine to peptidyl-citrulline, thereby reducing the positive charges and altering structure and function of proteins. Of the five PADs, PAD2 is the dominant isoform in the central nervous system (CNS). Abnormal PC and PAD dysregulation are associated with numerous pathological conditions, including inflammatory diseases and neurodegeneration. Animal model studies have shown therapeutic efficacy from inhibition of PADs, thus suggesting a role of PC in pathogenesis. To determine whether PC contribute to amyotrophic lateral sclerosis (ALS), a deadly neurodegenerative disease characterized by loss of motor neurons, paralysis, and eventual death, we investigated alterations of PC and PAD2 in two different transgenic mouse models of ALS expressing human mutant SOD1(G93A) and PFN1(C71G), respectively. PC and PAD2 expression are altered dynamically in the spinal cord during disease progression in both models. PC and PAD2 increase progressively in astrocytes with the development of reactive astrogliosis, while decreasing in neurons. Importantly, in the spinal cord white matter, PC accumulates in protein aggregates that contain the myelin proteins PLP and MBP. PC also accumulates progressively in insoluble protein fractions during disease progression. Finally, increased PC and PAD2 expression spatially correlate with areas of the CNS with the most severe motor neuron degeneration. These results suggest that altered PC is an integral part of the neurodegenerative process and potential biomarkers for disease progression in ALS. Moreover, increased PC may contribute to disease-associated processes such as myelin protein aggregation, myelin degeneration, and astrogliosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-022-01433-5. |
format | Online Article Text |
id | pubmed-9458309 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-94583092022-09-09 Protein citrullination marks myelin protein aggregation and disease progression in mouse ALS models Yusuf, Issa O. Qiao, Tao Parsi, Sepideh Tilvawala, Ronak Thompson, Paul R. Xu, Zuoshang Acta Neuropathol Commun Research Increased protein citrullination (PC) and dysregulated protein arginine deiminase (PAD) activity have been observed in several neurodegenerative diseases. PC is a posttranslational modification catalyzed by the PADs. PC converts peptidyl-arginine to peptidyl-citrulline, thereby reducing the positive charges and altering structure and function of proteins. Of the five PADs, PAD2 is the dominant isoform in the central nervous system (CNS). Abnormal PC and PAD dysregulation are associated with numerous pathological conditions, including inflammatory diseases and neurodegeneration. Animal model studies have shown therapeutic efficacy from inhibition of PADs, thus suggesting a role of PC in pathogenesis. To determine whether PC contribute to amyotrophic lateral sclerosis (ALS), a deadly neurodegenerative disease characterized by loss of motor neurons, paralysis, and eventual death, we investigated alterations of PC and PAD2 in two different transgenic mouse models of ALS expressing human mutant SOD1(G93A) and PFN1(C71G), respectively. PC and PAD2 expression are altered dynamically in the spinal cord during disease progression in both models. PC and PAD2 increase progressively in astrocytes with the development of reactive astrogliosis, while decreasing in neurons. Importantly, in the spinal cord white matter, PC accumulates in protein aggregates that contain the myelin proteins PLP and MBP. PC also accumulates progressively in insoluble protein fractions during disease progression. Finally, increased PC and PAD2 expression spatially correlate with areas of the CNS with the most severe motor neuron degeneration. These results suggest that altered PC is an integral part of the neurodegenerative process and potential biomarkers for disease progression in ALS. Moreover, increased PC may contribute to disease-associated processes such as myelin protein aggregation, myelin degeneration, and astrogliosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-022-01433-5. BioMed Central 2022-09-08 /pmc/articles/PMC9458309/ /pubmed/36076282 http://dx.doi.org/10.1186/s40478-022-01433-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Yusuf, Issa O. Qiao, Tao Parsi, Sepideh Tilvawala, Ronak Thompson, Paul R. Xu, Zuoshang Protein citrullination marks myelin protein aggregation and disease progression in mouse ALS models |
title | Protein citrullination marks myelin protein aggregation and disease progression in mouse ALS models |
title_full | Protein citrullination marks myelin protein aggregation and disease progression in mouse ALS models |
title_fullStr | Protein citrullination marks myelin protein aggregation and disease progression in mouse ALS models |
title_full_unstemmed | Protein citrullination marks myelin protein aggregation and disease progression in mouse ALS models |
title_short | Protein citrullination marks myelin protein aggregation and disease progression in mouse ALS models |
title_sort | protein citrullination marks myelin protein aggregation and disease progression in mouse als models |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9458309/ https://www.ncbi.nlm.nih.gov/pubmed/36076282 http://dx.doi.org/10.1186/s40478-022-01433-5 |
work_keys_str_mv | AT yusufissao proteincitrullinationmarksmyelinproteinaggregationanddiseaseprogressioninmousealsmodels AT qiaotao proteincitrullinationmarksmyelinproteinaggregationanddiseaseprogressioninmousealsmodels AT parsisepideh proteincitrullinationmarksmyelinproteinaggregationanddiseaseprogressioninmousealsmodels AT tilvawalaronak proteincitrullinationmarksmyelinproteinaggregationanddiseaseprogressioninmousealsmodels AT thompsonpaulr proteincitrullinationmarksmyelinproteinaggregationanddiseaseprogressioninmousealsmodels AT xuzuoshang proteincitrullinationmarksmyelinproteinaggregationanddiseaseprogressioninmousealsmodels |