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Inflammation Induces TDP-43 Mislocalization and Aggregation.

Correia AS, Patel P, Dutta K, Julien JP - PLoS ONE (2015)

Bottom Line: Likewise, treatment of the motoneuron-like NSC-34 cells with TNF-alpha (TNF-α) increased the cytoplasmic levels of TDP-43.In addition, the chronic intraperitoneal injection of LPS at a dose of 1mg/kg in TDP-43(A315T) transgenic mice exacerbated the pathological TDP-43 accumulation in the cytoplasm of spinal motor neurons and it enhanced the levels of TDP-43 aggregation.These results suggest that inflammation may contribute to development or exacerbation of TDP-43 proteinopathies in neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, 2705 Boulevard Laurier, Québec, QC, G1V 4G2, Canada.

ABSTRACT
TAR DNA-binding protein 43 (TDP-43) is a major component in aggregates of ubiquitinated proteins in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we report that lipopolysaccharide (LPS)-induced inflammation can promote TDP-43 mislocalization and aggregation. In culture, microglia and astrocytes exhibited TDP-43 mislocalization after exposure to LPS. Likewise, treatment of the motoneuron-like NSC-34 cells with TNF-alpha (TNF-α) increased the cytoplasmic levels of TDP-43. In addition, the chronic intraperitoneal injection of LPS at a dose of 1mg/kg in TDP-43(A315T) transgenic mice exacerbated the pathological TDP-43 accumulation in the cytoplasm of spinal motor neurons and it enhanced the levels of TDP-43 aggregation. These results suggest that inflammation may contribute to development or exacerbation of TDP-43 proteinopathies in neurodegenerative disorders.

No MeSH data available.


Related in: MedlinePlus

Cytoplasmic increase of TDP-43 in LPS-activated astrocytes.Representative images of astrocytes from hTDP-43A315T transgenic and non-transgenic littermates, treated or not treated with LPS (1 μg/ml) for one day. Astrocytes are double stained for TDP-43 (red) and GFAP (green) while nuclei are stained with DAPI (blue). Immunofluorescence for TDP-43 increased in the cytoplasm of LPS-treated astrocytes in both non transgenic (2nd panel) and transgenic culture (4th panel) as compared to the untreated control (1st and 3rd panel). However, the overall cytoplasmic increase of TDP-43 was more pronounced in LPS-treated astrocytes from hTDP-43A315T transgenic mice than in LPS-treated astrocytes from C57Bl6 mice. Arrows point on cells presenting a decrease in nuclear TDP-43. Scale bar 100μm.
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pone.0140248.g003: Cytoplasmic increase of TDP-43 in LPS-activated astrocytes.Representative images of astrocytes from hTDP-43A315T transgenic and non-transgenic littermates, treated or not treated with LPS (1 μg/ml) for one day. Astrocytes are double stained for TDP-43 (red) and GFAP (green) while nuclei are stained with DAPI (blue). Immunofluorescence for TDP-43 increased in the cytoplasm of LPS-treated astrocytes in both non transgenic (2nd panel) and transgenic culture (4th panel) as compared to the untreated control (1st and 3rd panel). However, the overall cytoplasmic increase of TDP-43 was more pronounced in LPS-treated astrocytes from hTDP-43A315T transgenic mice than in LPS-treated astrocytes from C57Bl6 mice. Arrows point on cells presenting a decrease in nuclear TDP-43. Scale bar 100μm.

Mentions: To test the effect of LPS on TDP-43 distribution in cytoplasm and nucleus of glial cells, primary glial cultures from non-transgenic and transgenic hTDP-43A315T mice were treated with 1μg/ml of LPS for 1 day. The sub-cellular localization of TDP-43 in astrocytes and microglia was analyzed by immunocytochemistry. Cell cultures were double stained for TDP-43 and GFAP (astrocyte marker) (Fig 3) or CD11b (microglia marker) (Fig 4).


Inflammation Induces TDP-43 Mislocalization and Aggregation.

Correia AS, Patel P, Dutta K, Julien JP - PLoS ONE (2015)

Cytoplasmic increase of TDP-43 in LPS-activated astrocytes.Representative images of astrocytes from hTDP-43A315T transgenic and non-transgenic littermates, treated or not treated with LPS (1 μg/ml) for one day. Astrocytes are double stained for TDP-43 (red) and GFAP (green) while nuclei are stained with DAPI (blue). Immunofluorescence for TDP-43 increased in the cytoplasm of LPS-treated astrocytes in both non transgenic (2nd panel) and transgenic culture (4th panel) as compared to the untreated control (1st and 3rd panel). However, the overall cytoplasmic increase of TDP-43 was more pronounced in LPS-treated astrocytes from hTDP-43A315T transgenic mice than in LPS-treated astrocytes from C57Bl6 mice. Arrows point on cells presenting a decrease in nuclear TDP-43. Scale bar 100μm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4596857&req=5

pone.0140248.g003: Cytoplasmic increase of TDP-43 in LPS-activated astrocytes.Representative images of astrocytes from hTDP-43A315T transgenic and non-transgenic littermates, treated or not treated with LPS (1 μg/ml) for one day. Astrocytes are double stained for TDP-43 (red) and GFAP (green) while nuclei are stained with DAPI (blue). Immunofluorescence for TDP-43 increased in the cytoplasm of LPS-treated astrocytes in both non transgenic (2nd panel) and transgenic culture (4th panel) as compared to the untreated control (1st and 3rd panel). However, the overall cytoplasmic increase of TDP-43 was more pronounced in LPS-treated astrocytes from hTDP-43A315T transgenic mice than in LPS-treated astrocytes from C57Bl6 mice. Arrows point on cells presenting a decrease in nuclear TDP-43. Scale bar 100μm.
Mentions: To test the effect of LPS on TDP-43 distribution in cytoplasm and nucleus of glial cells, primary glial cultures from non-transgenic and transgenic hTDP-43A315T mice were treated with 1μg/ml of LPS for 1 day. The sub-cellular localization of TDP-43 in astrocytes and microglia was analyzed by immunocytochemistry. Cell cultures were double stained for TDP-43 and GFAP (astrocyte marker) (Fig 3) or CD11b (microglia marker) (Fig 4).

Bottom Line: Likewise, treatment of the motoneuron-like NSC-34 cells with TNF-alpha (TNF-α) increased the cytoplasmic levels of TDP-43.In addition, the chronic intraperitoneal injection of LPS at a dose of 1mg/kg in TDP-43(A315T) transgenic mice exacerbated the pathological TDP-43 accumulation in the cytoplasm of spinal motor neurons and it enhanced the levels of TDP-43 aggregation.These results suggest that inflammation may contribute to development or exacerbation of TDP-43 proteinopathies in neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, 2705 Boulevard Laurier, Québec, QC, G1V 4G2, Canada.

ABSTRACT
TAR DNA-binding protein 43 (TDP-43) is a major component in aggregates of ubiquitinated proteins in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we report that lipopolysaccharide (LPS)-induced inflammation can promote TDP-43 mislocalization and aggregation. In culture, microglia and astrocytes exhibited TDP-43 mislocalization after exposure to LPS. Likewise, treatment of the motoneuron-like NSC-34 cells with TNF-alpha (TNF-α) increased the cytoplasmic levels of TDP-43. In addition, the chronic intraperitoneal injection of LPS at a dose of 1mg/kg in TDP-43(A315T) transgenic mice exacerbated the pathological TDP-43 accumulation in the cytoplasm of spinal motor neurons and it enhanced the levels of TDP-43 aggregation. These results suggest that inflammation may contribute to development or exacerbation of TDP-43 proteinopathies in neurodegenerative disorders.

No MeSH data available.


Related in: MedlinePlus