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Microglial lysosome dysfunction contributes to white matter pathology and TDP-43 proteinopathy in GRN-associated FTD

Loss-of-function mutations in the progranulin gene (GRN), which encodes progranulin (PGRN), are a major cause of frontotemporal dementia (FTD). GRN-associated FTD is characterized by TDP-43 inclusions and neuroinflammation, but how PGRN loss causes disease remains elusive. We show that Grn knockout...

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Autores principales: Wu, Yanwei, Shao, Wei, Todd, Tiffany W., Tong, Jimei, Yue, Mei, Koga, Shunsuke, Castanedes-Casey, Monica, Librero, Ariston L., Lee, Chris W., Mackenzie, Ian R., Dickson, Dennis W., Zhang, Yong-Jie, Petrucelli, Leonard, Prudencio, Mercedes
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491969/
https://www.ncbi.nlm.nih.gov/pubmed/34433069
http://dx.doi.org/10.1016/j.celrep.2021.109581
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author Wu, Yanwei
Shao, Wei
Todd, Tiffany W.
Tong, Jimei
Yue, Mei
Koga, Shunsuke
Castanedes-Casey, Monica
Librero, Ariston L.
Lee, Chris W.
Mackenzie, Ian R.
Dickson, Dennis W.
Zhang, Yong-Jie
Petrucelli, Leonard
Prudencio, Mercedes
author_facet Wu, Yanwei
Shao, Wei
Todd, Tiffany W.
Tong, Jimei
Yue, Mei
Koga, Shunsuke
Castanedes-Casey, Monica
Librero, Ariston L.
Lee, Chris W.
Mackenzie, Ian R.
Dickson, Dennis W.
Zhang, Yong-Jie
Petrucelli, Leonard
Prudencio, Mercedes
author_sort Wu, Yanwei
collection PubMed
description Loss-of-function mutations in the progranulin gene (GRN), which encodes progranulin (PGRN), are a major cause of frontotemporal dementia (FTD). GRN-associated FTD is characterized by TDP-43 inclusions and neuroinflammation, but how PGRN loss causes disease remains elusive. We show that Grn knockout (KO) mice have increased microgliosis in white matter and an accumulation of myelin debris in microglial lysosomes in the same regions. Accumulation of myelin debris is also observed in white matter of patients with GRN-associated FTD. In addition, our findings also suggest that PGRN insufficiency in microglia leads to impaired lysosomal-mediated clearance of myelin debris. Finally, Grn KO mice that are deficient in cathepsin D (Ctsd), a key lysosomal enzyme, have augmented myelin debris and increased neuronal TDP-43 pathology. Together, our data strongly imply that PGRN loss affects microglial activation and lysosomal function, resulting in the accumulation of myelin debris and contributing to TDP-43 pathology.
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spelling pubmed-84919692021-10-05 Microglial lysosome dysfunction contributes to white matter pathology and TDP-43 proteinopathy in GRN-associated FTD Wu, Yanwei Shao, Wei Todd, Tiffany W. Tong, Jimei Yue, Mei Koga, Shunsuke Castanedes-Casey, Monica Librero, Ariston L. Lee, Chris W. Mackenzie, Ian R. Dickson, Dennis W. Zhang, Yong-Jie Petrucelli, Leonard Prudencio, Mercedes Cell Rep Article Loss-of-function mutations in the progranulin gene (GRN), which encodes progranulin (PGRN), are a major cause of frontotemporal dementia (FTD). GRN-associated FTD is characterized by TDP-43 inclusions and neuroinflammation, but how PGRN loss causes disease remains elusive. We show that Grn knockout (KO) mice have increased microgliosis in white matter and an accumulation of myelin debris in microglial lysosomes in the same regions. Accumulation of myelin debris is also observed in white matter of patients with GRN-associated FTD. In addition, our findings also suggest that PGRN insufficiency in microglia leads to impaired lysosomal-mediated clearance of myelin debris. Finally, Grn KO mice that are deficient in cathepsin D (Ctsd), a key lysosomal enzyme, have augmented myelin debris and increased neuronal TDP-43 pathology. Together, our data strongly imply that PGRN loss affects microglial activation and lysosomal function, resulting in the accumulation of myelin debris and contributing to TDP-43 pathology. 2021-08-24 /pmc/articles/PMC8491969/ /pubmed/34433069 http://dx.doi.org/10.1016/j.celrep.2021.109581 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Wu, Yanwei
Shao, Wei
Todd, Tiffany W.
Tong, Jimei
Yue, Mei
Koga, Shunsuke
Castanedes-Casey, Monica
Librero, Ariston L.
Lee, Chris W.
Mackenzie, Ian R.
Dickson, Dennis W.
Zhang, Yong-Jie
Petrucelli, Leonard
Prudencio, Mercedes
Microglial lysosome dysfunction contributes to white matter pathology and TDP-43 proteinopathy in GRN-associated FTD
title Microglial lysosome dysfunction contributes to white matter pathology and TDP-43 proteinopathy in GRN-associated FTD
title_full Microglial lysosome dysfunction contributes to white matter pathology and TDP-43 proteinopathy in GRN-associated FTD
title_fullStr Microglial lysosome dysfunction contributes to white matter pathology and TDP-43 proteinopathy in GRN-associated FTD
title_full_unstemmed Microglial lysosome dysfunction contributes to white matter pathology and TDP-43 proteinopathy in GRN-associated FTD
title_short Microglial lysosome dysfunction contributes to white matter pathology and TDP-43 proteinopathy in GRN-associated FTD
title_sort microglial lysosome dysfunction contributes to white matter pathology and tdp-43 proteinopathy in grn-associated ftd
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491969/
https://www.ncbi.nlm.nih.gov/pubmed/34433069
http://dx.doi.org/10.1016/j.celrep.2021.109581
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