Axonopathy in an α-Synuclein Transgenic Model of Lewy Body Disease Is Associated with Extensive Accumulation of C-Terminal Truncated α-Synuclein

被引：82

作者：

Games, Dora ^{[1
]}

Seubert, Peter ^{[1
]}

Rockenstein, Edward ^{[2
]}

Patrick, Christina ^{[2
]}

Trejo, Margarita ^{[2
]}

Ubhi, Kiren ^{[2
]}

Ettle, Benjamin ^{[5
]}

Ghassemiam, Majid ^{[3
]}

Barbour, Robin ^{[1
]}

Schenk, Dale ^{[1
]}

Nuber, Silke ^{[2
]}

Masliah, Eliezer ^{[2
,4
]}

机构：

[1] Neotope Biosci, San Francisco, CA USA

[2] Univ Calif San Diego, Dept Neurosci, Biomol & Prote Mass Spectrometry Facil, La Jolla, CA 92093 USA

[3] Univ Calif San Diego, Dept Chem & Biochem, Biomol & Prote Mass Spectrometry Facil, La Jolla, CA 92093 USA

[4] Univ Calif San Diego, Dept Pathol, Biomol & Prote Mass Spectrometry Facil, La Jolla, CA 92093 USA

[5] Univ Hosp Erlangen, Dept Mol Neurol, Erlangen, Germany

来源：

AMERICAN JOURNAL OF PATHOLOGY | 2013年 / 182卷 / 03期

关键词：

PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; MOUSE MODEL; AXONAL-TRANSPORT; BODIES; MICE; DEMENTIA; AGGREGATION; CLEAVAGE; CALPAIN;

D O I：

10.1016/j.ajpath.2012.11.018

中图分类号：

R36 [病理学];

学科分类号：

100104 ;

摘要：

Progressive accumulation of alpha-synuclein (alpha-syn) in Limbic and striatonigral systems is associated with the neurodegenerative processes in dementia with Lewy bodies (DLB) and Parkinson's disease (PD). The mutine Thy-1 (mThy1)-alpha-syn transgenic (tg) model recapitulates aspects of degenerative processes associated with a-syn accumulation in these disorders. Given that axonal and synaptic pathologies are important features of DLB and PD, we sought to investigate the extent and characteristics of these alterations in mThy1-alpha-syn tg mice and to determine the contribution of alpha-syn c-terminally cleaved at amino acid 122 (CT alpha-syn) to these abnormalities. We generated a novel polyclonal antibody (SYN105) against the c-terminally truncated sequence (amino acids 121 to 123) of alpha-syn (CT alpha-syn) and performed immunocytochemical and ultrastructural analyses in mThy1-alpha-syn tg mice. We found abundant clusters of dystrophic neurites in Layers 2 to 3 of the neocortex, the stratum Lacunosum, the dentate gyrus, and cornu ammonis 3 of the hippocampus, striatum, thalamus, midbrain, and pons. Dystrophic neurites displayed intense immunoreactivity detected with the SYN105 antibody. Double-labeling studies with antibodies to phosphorylated neurofilaments confirmed the axonal Location of full-Length and CT alpha-syn. alpha-Syn immunoreactive dystrophic neurites contained numerous electrodense laminated structures. These results show that neuritic dystrophy is a prominent pathologic feature of the mThy1-alpha-syn tg model and suggest that CT alpha-syn might play an important role in the process of axonal damage in these mice as well as in DLB and PD. (Am J Pathol 2013, 182: 940-953; http://dx.doi.org/10.1016/j.ajpath.2012.11.018)

引用

页码：940 / 953

页数：14

共 70 条

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