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Differential regulation of progranulin derived granulin peptides

BACKGROUND: Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN is comprised of 7.5 granulin repeats and is processed into individual granulin peptides in the lysosome. However, very little is known about the levels and regulations of individ...

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Autores principales: Zhang, Tingting, Du, Huan, Santos, Mariela Nunez, Wu, Xiaochun, Pagan, Mitchell D., Trigiani, Lianne Jillian, Nishimura, Nozomi, Reinheckel, Thomas, Hu, Fenghua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8815130/
https://www.ncbi.nlm.nih.gov/pubmed/35120524
http://dx.doi.org/10.1186/s13024-021-00513-9
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author Zhang, Tingting
Du, Huan
Santos, Mariela Nunez
Wu, Xiaochun
Pagan, Mitchell D.
Trigiani, Lianne Jillian
Nishimura, Nozomi
Reinheckel, Thomas
Hu, Fenghua
author_facet Zhang, Tingting
Du, Huan
Santos, Mariela Nunez
Wu, Xiaochun
Pagan, Mitchell D.
Trigiani, Lianne Jillian
Nishimura, Nozomi
Reinheckel, Thomas
Hu, Fenghua
author_sort Zhang, Tingting
collection PubMed
description BACKGROUND: Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN is comprised of 7.5 granulin repeats and is processed into individual granulin peptides in the lysosome. However, very little is known about the levels and regulations of individual granulin peptides due to the lack of specific antibodies. RESULTS: Here we report the generation and characterization of antibodies specific to each granulin peptide. We found that the levels of granulins C, E and F are regulated differently  compared to granulins A and B in various tissues. The levels of PGRN and granulin peptides vary in different brain regions and the ratio between granulins and PGRN is highest in the cortical region in the adult male mouse brain. Granulin-A is localized in the lysosome in both neurons and microglia and its levels in microglia increase under pathological conditions. Interestingly,  the levels of granulin A in microglia change correspondingly with PGRN in response to stroke but not demyelination. Furthermore, deficiency of lysosomal proteases and the PGRN binding partner prosaposin leads to alterations in the ratios between individual granulin peptides. Granulins B, C and E are heavily glycosylated and the glycosylation patterns can be regulated under. CONCLUSION: Our results support that the levels of individual granulin peptides are differentially regulated under physiological and pathological conditions and provide novel insights into how granulin peptides function in the lysosome. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-021-00513-9.
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spelling pubmed-88151302022-02-07 Differential regulation of progranulin derived granulin peptides Zhang, Tingting Du, Huan Santos, Mariela Nunez Wu, Xiaochun Pagan, Mitchell D. Trigiani, Lianne Jillian Nishimura, Nozomi Reinheckel, Thomas Hu, Fenghua Mol Neurodegener Research Article BACKGROUND: Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN is comprised of 7.5 granulin repeats and is processed into individual granulin peptides in the lysosome. However, very little is known about the levels and regulations of individual granulin peptides due to the lack of specific antibodies. RESULTS: Here we report the generation and characterization of antibodies specific to each granulin peptide. We found that the levels of granulins C, E and F are regulated differently  compared to granulins A and B in various tissues. The levels of PGRN and granulin peptides vary in different brain regions and the ratio between granulins and PGRN is highest in the cortical region in the adult male mouse brain. Granulin-A is localized in the lysosome in both neurons and microglia and its levels in microglia increase under pathological conditions. Interestingly,  the levels of granulin A in microglia change correspondingly with PGRN in response to stroke but not demyelination. Furthermore, deficiency of lysosomal proteases and the PGRN binding partner prosaposin leads to alterations in the ratios between individual granulin peptides. Granulins B, C and E are heavily glycosylated and the glycosylation patterns can be regulated under. CONCLUSION: Our results support that the levels of individual granulin peptides are differentially regulated under physiological and pathological conditions and provide novel insights into how granulin peptides function in the lysosome. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-021-00513-9. BioMed Central 2022-02-04 /pmc/articles/PMC8815130/ /pubmed/35120524 http://dx.doi.org/10.1186/s13024-021-00513-9 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 Article
Zhang, Tingting
Du, Huan
Santos, Mariela Nunez
Wu, Xiaochun
Pagan, Mitchell D.
Trigiani, Lianne Jillian
Nishimura, Nozomi
Reinheckel, Thomas
Hu, Fenghua
Differential regulation of progranulin derived granulin peptides
title Differential regulation of progranulin derived granulin peptides
title_full Differential regulation of progranulin derived granulin peptides
title_fullStr Differential regulation of progranulin derived granulin peptides
title_full_unstemmed Differential regulation of progranulin derived granulin peptides
title_short Differential regulation of progranulin derived granulin peptides
title_sort differential regulation of progranulin derived granulin peptides
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8815130/
https://www.ncbi.nlm.nih.gov/pubmed/35120524
http://dx.doi.org/10.1186/s13024-021-00513-9
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