Transglutaminase 2 exacerbates alpha-synuclein toxicity in mice and yeast

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alpha-Synuclein is a key pathogenic protein that aggregates in hallmark lesions in Parkinson's disease and other alpha-synucleinopathies. Prior in vitro studies demonstrated that it is a substrate for cross-linking by transglutaminase 2 (TG2) into higher-order species. Here we investigated whether this increased aggregation occurs in vivo and whether TG2 exacerbates alpha-synuclein toxicity in Mus musculus and Saccharomyces cerevisiae. Compared with alpha-synuclein transgenic (Syn(Tg)) mice, animals double transgenic for human alpha-synuclein and TG2 (TG2(Tg)/Syn(Tg)) manifested greater high-molecular-weight insoluble species of alpha-synuclein in brain lysates and developed alpha-synuclein aggregates in the synaptic vesicle fraction. In addition, larger proteinase K-resistant aggregates developed, along with increased thioflavin-S-positive amyloid fibrils. This correlated with an exaggerated neuroinflammatory response, as seen with more astrocytes and microglia. Further neuronal damage was suggested by greater morphological disruption of nerve fibers and a trend toward decreased c-Fos immunoreactive neurons. Finally, the performance of TG2(Tg)/Syn(Tg) animals on motor behavioral tasks was worse relative to Syn(Tg) mice. Greater toxicity of alpha-synuclein was also demonstrated in yeast cells coexpressing TG2. Our findings demonstrate that TG2 promotes the aggregation of alpha-synuclein in vivo and that this is associated with aggravated toxicity of alpha-synuclein and its downstream neuropathologic consequences.
Publisher
FEDERATION AMER SOC EXP BIOL
Issue Date
2014-10
Language
English
Article Type
Article
Keywords

NEURONAL CELL-DEATH; PARKINSONS-DISEASE; TISSUE TRANSGLUTAMINASE; MOUSE MODEL; MEMBRANE INTERACTIONS; HUNTINGTONS-DISEASE; CROSS-LINKING; INHIBITION; BRAIN; NEURODEGENERATION

Citation

FASEB JOURNAL, v.28, no.10, pp.4280 - 4291

ISSN
0892-6638
DOI
10.1096/fj.14-251413
URI
http://hdl.handle.net/10203/202980
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