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Immunolocalization of influenza A virus and markers of inflammation in the human Parkinson's disease brain.

Rohn TT, Catlin LW - PLoS ONE (2011)

Bottom Line: Although much is known regarding the molecular mechanisms leading to neuronal cell loss in Parkinson's disease (PD), the initiating event has not been identified.Prevailing theories including a chemical insult or infectious agent have been postulated as possible triggers, leading to neuroinflammation.Further supporting a role for neuroinflammation in PD was the identification of T-lymphocytes that colocalized with an antibody to caspase-cleaved Beclin-1 within the SNpc.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Boise State University, Boise, Idaho, United States of America. trohn@boisestate.edu

ABSTRACT
Although much is known regarding the molecular mechanisms leading to neuronal cell loss in Parkinson's disease (PD), the initiating event has not been identified. Prevailing theories including a chemical insult or infectious agent have been postulated as possible triggers, leading to neuroinflammation. We present immunohistochemical data indicating the presence of influenza A virus within the substantia nigra pars compacta (SNpc) from postmortem PD brain sections. Influenza A virus labeling was identified within neuromelanin granules as well as on tissue macrophages in the SNpc. Further supporting a role for neuroinflammation in PD was the identification of T-lymphocytes that colocalized with an antibody to caspase-cleaved Beclin-1 within the SNpc. The presence of influenza A virus together with macrophages and T-lymphocytes may contribute to the neuroinflammation associated with this disease.

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Caspase-cleaved Beclin-1 in Parkinson's and dementia with Lewy body disease.(A–D): High (A and B) and low magnification (C and D), of representative single-labeling (blue) from a Parkinson's cases utilizing the BeclinCCP antibody illustrating staining of numerous small cells (<10 µm) in the SNpc (arrows, Fig. 1A) along with the staining of a single Lewy body (arrowhead, Fig. 1A). Comparative staining in representative age-matched control cases showing a general lack of staining with the BeclinCCP antibody (B and D). Brown structures (A–D) represent neuromelanin (asterisks), typical of neurons in the SNpc. (E): Representative labeling in a DLB case illustrating the “pearls-on-a-string” labeling with BeclinCCP in white matter within the SN (E, arrowheads). (F): Quantification of the number of BeclinCCP-positive cells within the SNpc for age-matched control cases (blue bar), PD cases, (red bar) and DLB cases (green bar). Results indicated a significant increase in the number of BeclinCCP-positive cells in both PD and DLB over control cases. Data represent the average (±S.E.M.) of three different fields taken with a 40× objective from five different cases. NS = no significant difference between PD and DLB cases (p = 0.331). *PD indicates significant difference between PD and control cases (p = 0.0005), and *DLB indicates significant difference between DLB and control cases (p = 0.0001). Scale bars are 10 µm in A, B, and E and 50 µm in C and D.
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pone-0020495-g001: Caspase-cleaved Beclin-1 in Parkinson's and dementia with Lewy body disease.(A–D): High (A and B) and low magnification (C and D), of representative single-labeling (blue) from a Parkinson's cases utilizing the BeclinCCP antibody illustrating staining of numerous small cells (<10 µm) in the SNpc (arrows, Fig. 1A) along with the staining of a single Lewy body (arrowhead, Fig. 1A). Comparative staining in representative age-matched control cases showing a general lack of staining with the BeclinCCP antibody (B and D). Brown structures (A–D) represent neuromelanin (asterisks), typical of neurons in the SNpc. (E): Representative labeling in a DLB case illustrating the “pearls-on-a-string” labeling with BeclinCCP in white matter within the SN (E, arrowheads). (F): Quantification of the number of BeclinCCP-positive cells within the SNpc for age-matched control cases (blue bar), PD cases, (red bar) and DLB cases (green bar). Results indicated a significant increase in the number of BeclinCCP-positive cells in both PD and DLB over control cases. Data represent the average (±S.E.M.) of three different fields taken with a 40× objective from five different cases. NS = no significant difference between PD and DLB cases (p = 0.331). *PD indicates significant difference between PD and control cases (p = 0.0005), and *DLB indicates significant difference between DLB and control cases (p = 0.0001). Scale bars are 10 µm in A, B, and E and 50 µm in C and D.

Mentions: Case demographics for PD cases are presented in Table S1 and age at death was not significantly different between PD (mean, 74.3±11.3), DLB (mean, 76.7±4.04) and controls (mean, 73.9±6.81). Representative pathology in PD cases including the presence of Lewy bodies and neurites, gliosis, and loss of dopaminergic neurons is depicted in Figure S1. The initial goal of our study was to examine whether the autophagic protein, Beclin-1, is caspase-cleaved in the PD brain. The Beclin-1 protein is essential for the proper execution of autophagy, a process that regulates the turnover of cellular constituents and evidence supports this vital function may be disrupted in PD [8], [9]. Previous studies have supported a loss of function of Beclin-1 due to proteolytic cleavage by caspases [10]. PD cases were analyzed for the presence of caspase-cleaved Beclin-1 following application of a site-directed caspase-cleavage antibody. We had previously used this antibody (herein termed the Beclin caspase-cleavage product (CCP) antibody) to demonstrate the caspase-cleavage of Beclin-1 within degenerating astrocytes and tangles of the Alzheimer's disease (AD) brain [11]. The BeclinCCP antibody is specific for the caspase-cleaved fragment of Beclin-1 in situ [11]. Surprisingly, the application of the BeclinCCP antibody in either PD or dementia with Lewy body (DLB) cases revealed labeling of numerous, small cells (<10 µm), throughout the SN (Fig. 1). Labeling was also observed in Lewy bodies (Fig. 1A), degenerating astrocytes (Fig. 2B), and apparent oligodendrocytes (Fig. 1E). There was a significant increase in the number of BeclinCCP-labeled cells as compared to age-matched controls (Fig. 1F).


Immunolocalization of influenza A virus and markers of inflammation in the human Parkinson's disease brain.

Rohn TT, Catlin LW - PLoS ONE (2011)

Caspase-cleaved Beclin-1 in Parkinson's and dementia with Lewy body disease.(A–D): High (A and B) and low magnification (C and D), of representative single-labeling (blue) from a Parkinson's cases utilizing the BeclinCCP antibody illustrating staining of numerous small cells (<10 µm) in the SNpc (arrows, Fig. 1A) along with the staining of a single Lewy body (arrowhead, Fig. 1A). Comparative staining in representative age-matched control cases showing a general lack of staining with the BeclinCCP antibody (B and D). Brown structures (A–D) represent neuromelanin (asterisks), typical of neurons in the SNpc. (E): Representative labeling in a DLB case illustrating the “pearls-on-a-string” labeling with BeclinCCP in white matter within the SN (E, arrowheads). (F): Quantification of the number of BeclinCCP-positive cells within the SNpc for age-matched control cases (blue bar), PD cases, (red bar) and DLB cases (green bar). Results indicated a significant increase in the number of BeclinCCP-positive cells in both PD and DLB over control cases. Data represent the average (±S.E.M.) of three different fields taken with a 40× objective from five different cases. NS = no significant difference between PD and DLB cases (p = 0.331). *PD indicates significant difference between PD and control cases (p = 0.0005), and *DLB indicates significant difference between DLB and control cases (p = 0.0001). Scale bars are 10 µm in A, B, and E and 50 µm in C and D.
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pone-0020495-g001: Caspase-cleaved Beclin-1 in Parkinson's and dementia with Lewy body disease.(A–D): High (A and B) and low magnification (C and D), of representative single-labeling (blue) from a Parkinson's cases utilizing the BeclinCCP antibody illustrating staining of numerous small cells (<10 µm) in the SNpc (arrows, Fig. 1A) along with the staining of a single Lewy body (arrowhead, Fig. 1A). Comparative staining in representative age-matched control cases showing a general lack of staining with the BeclinCCP antibody (B and D). Brown structures (A–D) represent neuromelanin (asterisks), typical of neurons in the SNpc. (E): Representative labeling in a DLB case illustrating the “pearls-on-a-string” labeling with BeclinCCP in white matter within the SN (E, arrowheads). (F): Quantification of the number of BeclinCCP-positive cells within the SNpc for age-matched control cases (blue bar), PD cases, (red bar) and DLB cases (green bar). Results indicated a significant increase in the number of BeclinCCP-positive cells in both PD and DLB over control cases. Data represent the average (±S.E.M.) of three different fields taken with a 40× objective from five different cases. NS = no significant difference between PD and DLB cases (p = 0.331). *PD indicates significant difference between PD and control cases (p = 0.0005), and *DLB indicates significant difference between DLB and control cases (p = 0.0001). Scale bars are 10 µm in A, B, and E and 50 µm in C and D.
Mentions: Case demographics for PD cases are presented in Table S1 and age at death was not significantly different between PD (mean, 74.3±11.3), DLB (mean, 76.7±4.04) and controls (mean, 73.9±6.81). Representative pathology in PD cases including the presence of Lewy bodies and neurites, gliosis, and loss of dopaminergic neurons is depicted in Figure S1. The initial goal of our study was to examine whether the autophagic protein, Beclin-1, is caspase-cleaved in the PD brain. The Beclin-1 protein is essential for the proper execution of autophagy, a process that regulates the turnover of cellular constituents and evidence supports this vital function may be disrupted in PD [8], [9]. Previous studies have supported a loss of function of Beclin-1 due to proteolytic cleavage by caspases [10]. PD cases were analyzed for the presence of caspase-cleaved Beclin-1 following application of a site-directed caspase-cleavage antibody. We had previously used this antibody (herein termed the Beclin caspase-cleavage product (CCP) antibody) to demonstrate the caspase-cleavage of Beclin-1 within degenerating astrocytes and tangles of the Alzheimer's disease (AD) brain [11]. The BeclinCCP antibody is specific for the caspase-cleaved fragment of Beclin-1 in situ [11]. Surprisingly, the application of the BeclinCCP antibody in either PD or dementia with Lewy body (DLB) cases revealed labeling of numerous, small cells (<10 µm), throughout the SN (Fig. 1). Labeling was also observed in Lewy bodies (Fig. 1A), degenerating astrocytes (Fig. 2B), and apparent oligodendrocytes (Fig. 1E). There was a significant increase in the number of BeclinCCP-labeled cells as compared to age-matched controls (Fig. 1F).

Bottom Line: Although much is known regarding the molecular mechanisms leading to neuronal cell loss in Parkinson's disease (PD), the initiating event has not been identified.Prevailing theories including a chemical insult or infectious agent have been postulated as possible triggers, leading to neuroinflammation.Further supporting a role for neuroinflammation in PD was the identification of T-lymphocytes that colocalized with an antibody to caspase-cleaved Beclin-1 within the SNpc.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Boise State University, Boise, Idaho, United States of America. trohn@boisestate.edu

ABSTRACT
Although much is known regarding the molecular mechanisms leading to neuronal cell loss in Parkinson's disease (PD), the initiating event has not been identified. Prevailing theories including a chemical insult or infectious agent have been postulated as possible triggers, leading to neuroinflammation. We present immunohistochemical data indicating the presence of influenza A virus within the substantia nigra pars compacta (SNpc) from postmortem PD brain sections. Influenza A virus labeling was identified within neuromelanin granules as well as on tissue macrophages in the SNpc. Further supporting a role for neuroinflammation in PD was the identification of T-lymphocytes that colocalized with an antibody to caspase-cleaved Beclin-1 within the SNpc. The presence of influenza A virus together with macrophages and T-lymphocytes may contribute to the neuroinflammation associated with this disease.

Show MeSH
Related in: MedlinePlus