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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

Translocation of TDP-43 from the nucleus to the cytoplasm in astrocytes and microglia with LPS-treatment.(A) Nuclear and cytoplasmic protein fractions of astrocytes were analyzed by Western blot. The intensity of the 43kDa TDP-43 bands was divided by the intensity of the respective actin band to take in account the differences in the protein loading. Fold change is the ratio of the 43 kDa band intensity in the LPS-treated cultures over the band intensity in the respective untreated controls, after normalized by the intensity of the correspondent actin bands.
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pone.0140248.g005: Translocation of TDP-43 from the nucleus to the cytoplasm in astrocytes and microglia with LPS-treatment.(A) Nuclear and cytoplasmic protein fractions of astrocytes were analyzed by Western blot. The intensity of the 43kDa TDP-43 bands was divided by the intensity of the respective actin band to take in account the differences in the protein loading. Fold change is the ratio of the 43 kDa band intensity in the LPS-treated cultures over the band intensity in the respective untreated controls, after normalized by the intensity of the correspondent actin bands.

Mentions: Subcellular fractionation of astrocyte cultures was performed. Nuclear and cytoplasmic fractions were analyzed by Western blot (Fig 5). TDP-43 was detected using a polyclonal antibody (Proteintech #10782-2-AP) which reacts with both human (transgenic) and mouse (endogenous) TDP-43. The intensity of TDP-43 bands was divided by the intensity of the respective actin band to take in account the differences in the protein loading. As shown in Fig 5, the treatment with LPS resulted in loss of TDP-43 protein in the nuclear fraction and in increased levels of TDP-43 in the cytoplasmic fraction.


Inflammation Induces TDP-43 Mislocalization and Aggregation.

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

Translocation of TDP-43 from the nucleus to the cytoplasm in astrocytes and microglia with LPS-treatment.(A) Nuclear and cytoplasmic protein fractions of astrocytes were analyzed by Western blot. The intensity of the 43kDa TDP-43 bands was divided by the intensity of the respective actin band to take in account the differences in the protein loading. Fold change is the ratio of the 43 kDa band intensity in the LPS-treated cultures over the band intensity in the respective untreated controls, after normalized by the intensity of the correspondent actin bands.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0140248.g005: Translocation of TDP-43 from the nucleus to the cytoplasm in astrocytes and microglia with LPS-treatment.(A) Nuclear and cytoplasmic protein fractions of astrocytes were analyzed by Western blot. The intensity of the 43kDa TDP-43 bands was divided by the intensity of the respective actin band to take in account the differences in the protein loading. Fold change is the ratio of the 43 kDa band intensity in the LPS-treated cultures over the band intensity in the respective untreated controls, after normalized by the intensity of the correspondent actin bands.
Mentions: Subcellular fractionation of astrocyte cultures was performed. Nuclear and cytoplasmic fractions were analyzed by Western blot (Fig 5). TDP-43 was detected using a polyclonal antibody (Proteintech #10782-2-AP) which reacts with both human (transgenic) and mouse (endogenous) TDP-43. The intensity of TDP-43 bands was divided by the intensity of the respective actin band to take in account the differences in the protein loading. As shown in Fig 5, the treatment with LPS resulted in loss of TDP-43 protein in the nuclear fraction and in increased levels of TDP-43 in the cytoplasmic fraction.

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