Distinct mechanisms of axonal globule formation in mice expressing human wild type α-synuclein or dementia with Lewy bodies-linked P123H ß-synuclein
<p>Abstract</p> <p>Background</p> <p>Axonopathy is critical in the early pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Axonal swellings such as globules and spheroids are a distinct feature of axonopa...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2012-09-01
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| Series: | Molecular Brain |
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| Online Access: | http://www.molecularbrain.com/content/5/1/34 |
| _version_ | 1828287572531478528 |
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| author | Sekigawa Akio Fujita Masayo Sekiyama Kazunari Takamatsu Yoshiki Hatano Taku Rockenstein Edward La Spada Albert R Masliah Eliezer Hashimoto Makoto |
| author_facet | Sekigawa Akio Fujita Masayo Sekiyama Kazunari Takamatsu Yoshiki Hatano Taku Rockenstein Edward La Spada Albert R Masliah Eliezer Hashimoto Makoto |
| author_sort | Sekigawa Akio |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Axonopathy is critical in the early pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Axonal swellings such as globules and spheroids are a distinct feature of axonopathy and our recent study showed that transgenic (tg) mice expressing DLB-linked P123H β-synuclein (P123H βS) were characterized by P123H βS-immunoreactive axonal swellings (P123H βS-globules). Therefore, the objectives of this study were to evaluate α-synuclein (αS)-immunoreactive axonal swellings (αS-globules) in the brains of tg mice expressing human wild-type αS and to compare them with the globules in P123H βS tg mice.</p> <p>Results</p> <p>In αS tg mice, αS-globules were formed in an age-dependent manner in various brain regions, including the thalamus and basal ganglia. These globules were composed of autophagosome-like membranous structures and were reminiscent of P123H βS-globules in P123H βS tg mice. In the αS-globules, frequent clustering and deformation of mitochondria were observed. These changes were associated with oxidative stress, based on staining of nitrated αS and 4-hydroxy-2-nonenal (4-HNE). In accord with the absence of mitochondria in the P123H βS-globules, staining of nitrated αS and 4-HNE in these globules was weaker than that for αS-globules. Leucine-rich repeat kinase 2 (LRRK2), the PARK8 of familial PD, was detected exclusively in αS-globules, suggesting a specific role of this molecule in these globules.</p> <p>Conclusions</p> <p>Lysosomal pathology was similarly observed for both αS- and P123H βS-globules, while oxidative stress was associated with the αS-globules, and to a lesser extent with the P123H βS-globules. Other pathologies, such as mitochondrial alteration and LRRK2 accumulation, were exclusively detected for αS-globules. Collectively, both αS- and P123H βS-globules were formed through similar but distinct pathogenic mechanisms. Our findings suggest that synuclein family members might contribute to diverse axonal pathologies.</p> |
| first_indexed | 2024-04-13T09:51:04Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1756-6606 |
| language | English |
| last_indexed | 2024-04-13T09:51:04Z |
| publishDate | 2012-09-01 |
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| series | Molecular Brain |
| spelling | doaj.art-800de3e6221949089fce428d3349fc6d2022-12-22T02:51:36ZengBMCMolecular Brain1756-66062012-09-01513410.1186/1756-6606-5-34Distinct mechanisms of axonal globule formation in mice expressing human wild type α-synuclein or dementia with Lewy bodies-linked P123H ß-synucleinSekigawa AkioFujita MasayoSekiyama KazunariTakamatsu YoshikiHatano TakuRockenstein EdwardLa Spada Albert RMasliah EliezerHashimoto Makoto<p>Abstract</p> <p>Background</p> <p>Axonopathy is critical in the early pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Axonal swellings such as globules and spheroids are a distinct feature of axonopathy and our recent study showed that transgenic (tg) mice expressing DLB-linked P123H β-synuclein (P123H βS) were characterized by P123H βS-immunoreactive axonal swellings (P123H βS-globules). Therefore, the objectives of this study were to evaluate α-synuclein (αS)-immunoreactive axonal swellings (αS-globules) in the brains of tg mice expressing human wild-type αS and to compare them with the globules in P123H βS tg mice.</p> <p>Results</p> <p>In αS tg mice, αS-globules were formed in an age-dependent manner in various brain regions, including the thalamus and basal ganglia. These globules were composed of autophagosome-like membranous structures and were reminiscent of P123H βS-globules in P123H βS tg mice. In the αS-globules, frequent clustering and deformation of mitochondria were observed. These changes were associated with oxidative stress, based on staining of nitrated αS and 4-hydroxy-2-nonenal (4-HNE). In accord with the absence of mitochondria in the P123H βS-globules, staining of nitrated αS and 4-HNE in these globules was weaker than that for αS-globules. Leucine-rich repeat kinase 2 (LRRK2), the PARK8 of familial PD, was detected exclusively in αS-globules, suggesting a specific role of this molecule in these globules.</p> <p>Conclusions</p> <p>Lysosomal pathology was similarly observed for both αS- and P123H βS-globules, while oxidative stress was associated with the αS-globules, and to a lesser extent with the P123H βS-globules. Other pathologies, such as mitochondrial alteration and LRRK2 accumulation, were exclusively detected for αS-globules. Collectively, both αS- and P123H βS-globules were formed through similar but distinct pathogenic mechanisms. Our findings suggest that synuclein family members might contribute to diverse axonal pathologies.</p>http://www.molecularbrain.com/content/5/1/34α-synucleinP123H β-synucleinParkinson’s diseaseMitochondriaLysosomeTransgenic mouse |
| spellingShingle | Sekigawa Akio Fujita Masayo Sekiyama Kazunari Takamatsu Yoshiki Hatano Taku Rockenstein Edward La Spada Albert R Masliah Eliezer Hashimoto Makoto Distinct mechanisms of axonal globule formation in mice expressing human wild type α-synuclein or dementia with Lewy bodies-linked P123H ß-synuclein Molecular Brain α-synuclein P123H β-synuclein Parkinson’s disease Mitochondria Lysosome Transgenic mouse |
| title | Distinct mechanisms of axonal globule formation in mice expressing human wild type α-synuclein or dementia with Lewy bodies-linked P123H ß-synuclein |
| title_full | Distinct mechanisms of axonal globule formation in mice expressing human wild type α-synuclein or dementia with Lewy bodies-linked P123H ß-synuclein |
| title_fullStr | Distinct mechanisms of axonal globule formation in mice expressing human wild type α-synuclein or dementia with Lewy bodies-linked P123H ß-synuclein |
| title_full_unstemmed | Distinct mechanisms of axonal globule formation in mice expressing human wild type α-synuclein or dementia with Lewy bodies-linked P123H ß-synuclein |
| title_short | Distinct mechanisms of axonal globule formation in mice expressing human wild type α-synuclein or dementia with Lewy bodies-linked P123H ß-synuclein |
| title_sort | distinct mechanisms of axonal globule formation in mice expressing human wild type α synuclein or dementia with lewy bodies linked p123h ss synuclein |
| topic | α-synuclein P123H β-synuclein Parkinson’s disease Mitochondria Lysosome Transgenic mouse |
| url | http://www.molecularbrain.com/content/5/1/34 |
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