Details

Autor(en) / Beteiligte

• Grosso, Hilary
• Woo, Jong‐Min
• Lee, Kang‐Woo
• Im, Joo‐Young
• Masliah, Eliezer
• Junn, Eunsung
• Mouradian, M. Maral

Titel

Transglutaminase 2 exacerbates α‐synuclein toxicity in mice and yeast

Ist Teil von

• The FASEB journal, 2014-10, Vol.28 (10), p.4280-4291

Ort / Verlag

Bethesda, MD, USA: Federation of American Societies for Experimental Biology

Erscheinungsjahr

2014

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• α‐Synuclein is a key pathogenic protein that aggregates in hallmark lesions in Parkinson's disease and other α‐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 α‐synuclein toxicity in Mus musculus and Saccharomyces cerevisiae. Compared with α‐synuclein transgenic (SynTg) mice, animals double transgenic for human α‐synuclein and TG2 (TG2Tg/SynTg) manifested greater high‐molecular‐weight insoluble species of α‐synuclein in brain lysates and developed α‐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 TG2Tg/SynTg animals on motor behavioral tasks was worse relative to SynTg mice. Greater toxicity of α‐synuclein was also demonstrated in yeast cells coexpressing TG2. Our findings demonstrate that TG2 promotes the aggregation of α‐synuclein in vivo and that this is associated with aggravated toxicity of α‐synuclein and its downstream neuropathologic consequences.—Grosso, H., Woo, J.‐M., Lee, K.W., Im, J.‐Y., Masliah, E., Junn, E., Mouradian, M. M., Transglutaminase 2 exacerbates α‐synuclein toxicity in mice and yeast. FASEB J. 28, 4280–4291 (2014). www.fasebj.org