Limits...
Protein Citrullination: A Proposed Mechanism for Pathology in Traumatic Brain Injury.

Lazarus RC, Buonora JE, Flora MN, Freedy JG, Holstein GR, Martinelli GP, Jacobowitz DM, Mueller GP - Front Neurol (2015)

Bottom Line: The present investigation addressed this gap by examining the effects of TBI on the distribution of protein citrullination and on the specific cell types involved.This response was exclusively seen in astrocytes; no such effects were observed on the status of protein citrullination in neurons, oligodendrocytes or microglia.Further, proteomic analyses demonstrated that the effects of TBI on citrullination were confined to a relatively small subset of neural proteins.

View Article: PubMed Central - PubMed

Affiliation: Program in Neuroscience, Uniformed Services University of the Health Sciences , Bethesda, MD , USA.

ABSTRACT
Protein citrullination is a calcium-driven post-translational modification proposed to play a causative role in the neurodegenerative disorders of Alzheimer's disease, multiple sclerosis (MS), and prion disease. Citrullination can result in the formation of antigenic epitopes that underlie pathogenic autoimmune responses. This phenomenon, which is best understood in rheumatoid arthritis, may play a role in the chronic dysfunction following traumatic brain injury (TBI). Despite substantial evidence of aberrations in calcium signaling following TBI, there is little understanding of how TBI alters citrullination in the brain. The present investigation addressed this gap by examining the effects of TBI on the distribution of protein citrullination and on the specific cell types involved. Immunofluorescence revealed that controlled cortical impact in rats profoundly up--regulated protein citrullination in the cerebral cortex, external capsule, and hippocampus. This response was exclusively seen in astrocytes; no such effects were observed on the status of protein citrullination in neurons, oligodendrocytes or microglia. Further, proteomic analyses demonstrated that the effects of TBI on citrullination were confined to a relatively small subset of neural proteins. Proteins most notably affected were those also reported to be citrullinated in other disorders, including prion disease and MS. In vivo findings were extended in an in vitro model of simulated TBI employing normal human astrocytes. Pharmacologically induced calcium excitotoxicity was shown to activate the citrullination and breakdown of glial fibrillary acidic protein, producing a novel candidate TBI biomarker and potential target for autoimmune recognition. In summary, these findings demonstrate that the effects of TBI on protein citrullination are selective with respect to brain region, cell type, and proteins modified, and may contribute to a role for autoimmune dysfunction in chronic pathology following TBI.

No MeSH data available.


Related in: MedlinePlus

Injury upregulates the expression of citrullinated proteins in the cerebral cortex. Brain tissue was collected 5 days after CCI and evaluated for protein citrullination by anti-protein citrulline immunolabeling using mAB 6B3. The upper panels show immunolabeling in sections of control (left) and injured brain (right) (2× magnification). Lower panels show higher magnifications of cerebral cortex adjacent to the lesion site (right) or a comparable site in control cortex (left) (20× magnification). Data are representative of 15 control animals (8 males and 7 females) and 21 CCI animals (11 males and 10 females). No gender-based differences were observed. PB-cit, protein-bound citrulline.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4585288&req=5

Figure 1: Injury upregulates the expression of citrullinated proteins in the cerebral cortex. Brain tissue was collected 5 days after CCI and evaluated for protein citrullination by anti-protein citrulline immunolabeling using mAB 6B3. The upper panels show immunolabeling in sections of control (left) and injured brain (right) (2× magnification). Lower panels show higher magnifications of cerebral cortex adjacent to the lesion site (right) or a comparable site in control cortex (left) (20× magnification). Data are representative of 15 control animals (8 males and 7 females) and 21 CCI animals (11 males and 10 females). No gender-based differences were observed. PB-cit, protein-bound citrulline.

Mentions: Figure 1 presents the effects of CCI on the expression of citrullinated proteins in the rat cerebral cortex. Immunohistochemical analysis demonstrated that the basal level of protein citrullination as detected by labeling with mAB 6B3 was very low under control conditions. In contrast, CCI induced a marked increase in the immunolabeling of cells in the cortex. This up-regulation of protein citrullination was most pronounced in the vicinity of the lesion. The morphology of the affected cells was remarkably consistent, suggesting that the effects of CCI on protein citrullination were cell specific.


Protein Citrullination: A Proposed Mechanism for Pathology in Traumatic Brain Injury.

Lazarus RC, Buonora JE, Flora MN, Freedy JG, Holstein GR, Martinelli GP, Jacobowitz DM, Mueller GP - Front Neurol (2015)

Injury upregulates the expression of citrullinated proteins in the cerebral cortex. Brain tissue was collected 5 days after CCI and evaluated for protein citrullination by anti-protein citrulline immunolabeling using mAB 6B3. The upper panels show immunolabeling in sections of control (left) and injured brain (right) (2× magnification). Lower panels show higher magnifications of cerebral cortex adjacent to the lesion site (right) or a comparable site in control cortex (left) (20× magnification). Data are representative of 15 control animals (8 males and 7 females) and 21 CCI animals (11 males and 10 females). No gender-based differences were observed. PB-cit, protein-bound citrulline.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585288&req=5

Figure 1: Injury upregulates the expression of citrullinated proteins in the cerebral cortex. Brain tissue was collected 5 days after CCI and evaluated for protein citrullination by anti-protein citrulline immunolabeling using mAB 6B3. The upper panels show immunolabeling in sections of control (left) and injured brain (right) (2× magnification). Lower panels show higher magnifications of cerebral cortex adjacent to the lesion site (right) or a comparable site in control cortex (left) (20× magnification). Data are representative of 15 control animals (8 males and 7 females) and 21 CCI animals (11 males and 10 females). No gender-based differences were observed. PB-cit, protein-bound citrulline.
Mentions: Figure 1 presents the effects of CCI on the expression of citrullinated proteins in the rat cerebral cortex. Immunohistochemical analysis demonstrated that the basal level of protein citrullination as detected by labeling with mAB 6B3 was very low under control conditions. In contrast, CCI induced a marked increase in the immunolabeling of cells in the cortex. This up-regulation of protein citrullination was most pronounced in the vicinity of the lesion. The morphology of the affected cells was remarkably consistent, suggesting that the effects of CCI on protein citrullination were cell specific.

Bottom Line: The present investigation addressed this gap by examining the effects of TBI on the distribution of protein citrullination and on the specific cell types involved.This response was exclusively seen in astrocytes; no such effects were observed on the status of protein citrullination in neurons, oligodendrocytes or microglia.Further, proteomic analyses demonstrated that the effects of TBI on citrullination were confined to a relatively small subset of neural proteins.

View Article: PubMed Central - PubMed

Affiliation: Program in Neuroscience, Uniformed Services University of the Health Sciences , Bethesda, MD , USA.

ABSTRACT
Protein citrullination is a calcium-driven post-translational modification proposed to play a causative role in the neurodegenerative disorders of Alzheimer's disease, multiple sclerosis (MS), and prion disease. Citrullination can result in the formation of antigenic epitopes that underlie pathogenic autoimmune responses. This phenomenon, which is best understood in rheumatoid arthritis, may play a role in the chronic dysfunction following traumatic brain injury (TBI). Despite substantial evidence of aberrations in calcium signaling following TBI, there is little understanding of how TBI alters citrullination in the brain. The present investigation addressed this gap by examining the effects of TBI on the distribution of protein citrullination and on the specific cell types involved. Immunofluorescence revealed that controlled cortical impact in rats profoundly up--regulated protein citrullination in the cerebral cortex, external capsule, and hippocampus. This response was exclusively seen in astrocytes; no such effects were observed on the status of protein citrullination in neurons, oligodendrocytes or microglia. Further, proteomic analyses demonstrated that the effects of TBI on citrullination were confined to a relatively small subset of neural proteins. Proteins most notably affected were those also reported to be citrullinated in other disorders, including prion disease and MS. In vivo findings were extended in an in vitro model of simulated TBI employing normal human astrocytes. Pharmacologically induced calcium excitotoxicity was shown to activate the citrullination and breakdown of glial fibrillary acidic protein, producing a novel candidate TBI biomarker and potential target for autoimmune recognition. In summary, these findings demonstrate that the effects of TBI on protein citrullination are selective with respect to brain region, cell type, and proteins modified, and may contribute to a role for autoimmune dysfunction in chronic pathology following TBI.

No MeSH data available.


Related in: MedlinePlus