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Expression of TMEM106B, the frontotemporal lobar degeneration-associated protein, in normal and diseased human brain
BACKGROUND: Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementia in individuals under 65 years old and manifests as alterations in behavior, personality, or language secondary to degeneration of the frontal and/or temporal lobes. FTLD-TDP, the largest neuropathologica...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893524/ https://www.ncbi.nlm.nih.gov/pubmed/24252750 http://dx.doi.org/10.1186/2051-5960-1-36 |
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author | Busch, Johanna I Martinez-Lage, Maria Ashbridge, Emily Grossman, Murray Van Deerlin, Vivianna M Hu, Fenghua Lee, Virginia MY Trojanowski, John Q Chen-Plotkin, Alice S |
author_facet | Busch, Johanna I Martinez-Lage, Maria Ashbridge, Emily Grossman, Murray Van Deerlin, Vivianna M Hu, Fenghua Lee, Virginia MY Trojanowski, John Q Chen-Plotkin, Alice S |
author_sort | Busch, Johanna I |
collection | PubMed |
description | BACKGROUND: Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementia in individuals under 65 years old and manifests as alterations in behavior, personality, or language secondary to degeneration of the frontal and/or temporal lobes. FTLD-TDP, the largest neuropathological subset of FTLD, is characterized by hyperphosphorylated, ubiquitinated TAR DNA-binding protein 43 (TDP-43) inclusions. Mutations in progranulin (GRN), a neuroprotective growth factor, are one of the most common Mendelian genetic causes of FTLD-TDP. Moreover, a recent genome-wide association study (GWAS) identified multiple SNPs within the uncharacterized gene TMEM106B that significantly associated with FTLD-TDP, suggesting that TMEM106B genotype confers risk for FTLD-TDP. Indeed, TMEM106B expression levels, which correlate with TMEM106B genotype, may play a role in the pathogenesis of disease. RESULTS: Since little is known about TMEM106B and its expression in human brain, we performed immunohistochemical studies of TMEM106B in postmortem human brain samples from normal individuals, FTLD-TDP individuals with and without GRN mutations, and individuals with other neurodegenerative diseases. We find that TMEM106B protein is cytoplasmically expressed in both histopathologically affected and unaffected areas of the brain by neurons, glia, and endothelial cells/pericytes. Furthermore, we demonstrate that TMEM106B expression may differ among neuronal subtypes. Finally, we show that TMEM106B neuronal expression is significantly more disorganized in FTLD-TDP cases with GRN mutations, compared to normal and disease controls, including FTLD-TDP cases without GRN mutations. CONCLUSIONS: Our data provide an initial neuropathological characterization of the newly discovered FTLD-TDP-associated protein TMEM106B. In addition, we demonstrate that FTLD-TDP cases with GRN mutations exhibit a loss of neuronal TMEM106B subcellular localization, adding to evidence that TMEM106B and progranulin may be pathophysiologically linked in FTLD-TDP. |
format | Online Article Text |
id | pubmed-3893524 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-38935242014-01-17 Expression of TMEM106B, the frontotemporal lobar degeneration-associated protein, in normal and diseased human brain Busch, Johanna I Martinez-Lage, Maria Ashbridge, Emily Grossman, Murray Van Deerlin, Vivianna M Hu, Fenghua Lee, Virginia MY Trojanowski, John Q Chen-Plotkin, Alice S Acta Neuropathol Commun Research BACKGROUND: Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementia in individuals under 65 years old and manifests as alterations in behavior, personality, or language secondary to degeneration of the frontal and/or temporal lobes. FTLD-TDP, the largest neuropathological subset of FTLD, is characterized by hyperphosphorylated, ubiquitinated TAR DNA-binding protein 43 (TDP-43) inclusions. Mutations in progranulin (GRN), a neuroprotective growth factor, are one of the most common Mendelian genetic causes of FTLD-TDP. Moreover, a recent genome-wide association study (GWAS) identified multiple SNPs within the uncharacterized gene TMEM106B that significantly associated with FTLD-TDP, suggesting that TMEM106B genotype confers risk for FTLD-TDP. Indeed, TMEM106B expression levels, which correlate with TMEM106B genotype, may play a role in the pathogenesis of disease. RESULTS: Since little is known about TMEM106B and its expression in human brain, we performed immunohistochemical studies of TMEM106B in postmortem human brain samples from normal individuals, FTLD-TDP individuals with and without GRN mutations, and individuals with other neurodegenerative diseases. We find that TMEM106B protein is cytoplasmically expressed in both histopathologically affected and unaffected areas of the brain by neurons, glia, and endothelial cells/pericytes. Furthermore, we demonstrate that TMEM106B expression may differ among neuronal subtypes. Finally, we show that TMEM106B neuronal expression is significantly more disorganized in FTLD-TDP cases with GRN mutations, compared to normal and disease controls, including FTLD-TDP cases without GRN mutations. CONCLUSIONS: Our data provide an initial neuropathological characterization of the newly discovered FTLD-TDP-associated protein TMEM106B. In addition, we demonstrate that FTLD-TDP cases with GRN mutations exhibit a loss of neuronal TMEM106B subcellular localization, adding to evidence that TMEM106B and progranulin may be pathophysiologically linked in FTLD-TDP. BioMed Central 2013-07-11 /pmc/articles/PMC3893524/ /pubmed/24252750 http://dx.doi.org/10.1186/2051-5960-1-36 Text en Copyright © 2013 Busch et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Busch, Johanna I Martinez-Lage, Maria Ashbridge, Emily Grossman, Murray Van Deerlin, Vivianna M Hu, Fenghua Lee, Virginia MY Trojanowski, John Q Chen-Plotkin, Alice S Expression of TMEM106B, the frontotemporal lobar degeneration-associated protein, in normal and diseased human brain |
title | Expression of TMEM106B, the frontotemporal lobar degeneration-associated protein, in normal and diseased human brain |
title_full | Expression of TMEM106B, the frontotemporal lobar degeneration-associated protein, in normal and diseased human brain |
title_fullStr | Expression of TMEM106B, the frontotemporal lobar degeneration-associated protein, in normal and diseased human brain |
title_full_unstemmed | Expression of TMEM106B, the frontotemporal lobar degeneration-associated protein, in normal and diseased human brain |
title_short | Expression of TMEM106B, the frontotemporal lobar degeneration-associated protein, in normal and diseased human brain |
title_sort | expression of tmem106b, the frontotemporal lobar degeneration-associated protein, in normal and diseased human brain |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893524/ https://www.ncbi.nlm.nih.gov/pubmed/24252750 http://dx.doi.org/10.1186/2051-5960-1-36 |
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