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Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

INTRODUCTION: It has been shown that progranulin (PGRN) deficiency causes age-related neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Previous studies also suggested that PGRN is involved in modulating...

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Autores principales: Tanaka, Yoshinori, Chambers, James K, Matsuwaki, Takashi, Yamanouchi, Keitaro, Nishihara, Masugi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149276/
https://www.ncbi.nlm.nih.gov/pubmed/25022663
http://dx.doi.org/10.1186/s40478-014-0078-x
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author Tanaka, Yoshinori
Chambers, James K
Matsuwaki, Takashi
Yamanouchi, Keitaro
Nishihara, Masugi
author_facet Tanaka, Yoshinori
Chambers, James K
Matsuwaki, Takashi
Yamanouchi, Keitaro
Nishihara, Masugi
author_sort Tanaka, Yoshinori
collection PubMed
description INTRODUCTION: It has been shown that progranulin (PGRN) deficiency causes age-related neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Previous studies also suggested that PGRN is involved in modulating lysosomal function. To elucidate the pathophysiological role of PGRN in the aged brain, in the present study, lysosomal function and pathological changes of the brain were investigated using 10- and 90-week-old wild-type and PGRN-deficient mice. RESULTS: We showed that PGRN deficiency caused enhanced CD68 expression in activated microglia and astrogliosis in the cortex and thalamus, especially in the ventral posteromedial nucleus/ventral posterolateral nucleus (VPM/VPL), in the aged brain. Immunoreactivity for Lamp1 (lysosome marker) in the VPM/VPL and expression of lysosome-related genes, i.e. cathepsin D, V-type proton ATPase subunit d2, and transcription factor EB genes, were also increased by PGRN deficiency. Aggregates of p62, which is selectively degraded by the autophagy-lysosomal system, were observed in neuronal and glial cells in the VPM/VPL of aged PGRN-deficient mice. TAR DNA binding protein 43 (TDP-43) aggregates in the cytoplasm of neurons were also observed in aged PGRN-deficient mice. PGRN deficiency caused enhanced expression of glial cell-derived cytotoxic factors such as macrophage expressed gene 1, cytochrome b-245 light chain, cytochrome b-245 heavy chain, complement C4, tumor necrosis factor-α and lipocalin 2. In addition, neuronal loss and lipofuscinosis in the VPM/VPL and disrupted myelination in the cerebral cortex were observed in aged PGRN-deficient mice. CONCLUSIONS: The present study shows that aged PGRN-deficient mice present with NCL-like pathology as well as TDP-43 aggregates in the VPM/VPL, where a particular vulnerability has been reported in NCL model mice. The present results also suggest that these pathological changes in the VPM/VPL are likely a result of lysosomal dysfunction. How PGRN prevents lysosomal dysfunction with aging remains to be elucidated. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-014-0078-x) contains supplementary material, which is available to authorized users.
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spelling pubmed-41492762014-08-30 Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice Tanaka, Yoshinori Chambers, James K Matsuwaki, Takashi Yamanouchi, Keitaro Nishihara, Masugi Acta Neuropathol Commun Research INTRODUCTION: It has been shown that progranulin (PGRN) deficiency causes age-related neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Previous studies also suggested that PGRN is involved in modulating lysosomal function. To elucidate the pathophysiological role of PGRN in the aged brain, in the present study, lysosomal function and pathological changes of the brain were investigated using 10- and 90-week-old wild-type and PGRN-deficient mice. RESULTS: We showed that PGRN deficiency caused enhanced CD68 expression in activated microglia and astrogliosis in the cortex and thalamus, especially in the ventral posteromedial nucleus/ventral posterolateral nucleus (VPM/VPL), in the aged brain. Immunoreactivity for Lamp1 (lysosome marker) in the VPM/VPL and expression of lysosome-related genes, i.e. cathepsin D, V-type proton ATPase subunit d2, and transcription factor EB genes, were also increased by PGRN deficiency. Aggregates of p62, which is selectively degraded by the autophagy-lysosomal system, were observed in neuronal and glial cells in the VPM/VPL of aged PGRN-deficient mice. TAR DNA binding protein 43 (TDP-43) aggregates in the cytoplasm of neurons were also observed in aged PGRN-deficient mice. PGRN deficiency caused enhanced expression of glial cell-derived cytotoxic factors such as macrophage expressed gene 1, cytochrome b-245 light chain, cytochrome b-245 heavy chain, complement C4, tumor necrosis factor-α and lipocalin 2. In addition, neuronal loss and lipofuscinosis in the VPM/VPL and disrupted myelination in the cerebral cortex were observed in aged PGRN-deficient mice. CONCLUSIONS: The present study shows that aged PGRN-deficient mice present with NCL-like pathology as well as TDP-43 aggregates in the VPM/VPL, where a particular vulnerability has been reported in NCL model mice. The present results also suggest that these pathological changes in the VPM/VPL are likely a result of lysosomal dysfunction. How PGRN prevents lysosomal dysfunction with aging remains to be elucidated. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-014-0078-x) contains supplementary material, which is available to authorized users. BioMed Central 2014-07-15 /pmc/articles/PMC4149276/ /pubmed/25022663 http://dx.doi.org/10.1186/s40478-014-0078-x Text en © Tanaka et al.; licensee BioMed Central Ltd. 2014
spellingShingle Research
Tanaka, Yoshinori
Chambers, James K
Matsuwaki, Takashi
Yamanouchi, Keitaro
Nishihara, Masugi
Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice
title Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice
title_full Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice
title_fullStr Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice
title_full_unstemmed Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice
title_short Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice
title_sort possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149276/
https://www.ncbi.nlm.nih.gov/pubmed/25022663
http://dx.doi.org/10.1186/s40478-014-0078-x
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