Basso, Manuela and Berlin, Jill and Xia, Li and Sleiman, Sama F and Ko, Brendan and Haskew-Layton, Renee and Kim, Eunhee and Antonyak, Marc A and Cerione, Richard A and Iismaa, Siiri E and Willis, Dianna and Cho, Sunghee and Ratan, Rajiv R (2012) Transglutaminase inhibition protects against oxidative stress-induced neuronal death downstream of pathological ERK activation. The Journal of neuroscience, 32 (19). pp.6561-9. ISSN 1529-2401 (PMC OA)
Full text not available from this repository.Abstract
Molecular deletion of transglutaminase 2 (TG2) has been shown to improve function and survival in a host of neurological conditions including stroke, Huntington's disease, and Parkinson's disease. However, unifying schemes by which these cross-linking or polyaminating enzymes participate broadly in neuronal death have yet to be presented. Unexpectedly, we found that in addition to TG2, TG1 gene expression level is significantly induced following stroke in vivo or due to oxidative stress in vitro. Forced expression of TG1 or TG2 proteins is sufficient to induce neuronal death in Rattus norvegicus cortical neurons in vitro. Accordingly, molecular deletion of TG2 alone is insufficient to protect Mus musculus neurons from oxidative death. By contrast, structurally diverse inhibitors used at concentrations that inhibit TG1 and TG2 simultaneously are neuroprotective. These small molecules inhibit increases in neuronal transamidating activity induced by oxidative stress; they also protect neurons downstream of pathological ERK activation when added well after the onset of the death stimulus. Together, these studies suggest that multiple TG isoforms, not only TG2, participate in oxidative stress-induced cell death signaling; and that isoform nonselective inhibitors of TG will be most efficacious in combating oxidative death in neurological disorders.
(National Institute of Health NIH P01 NIA AG014930, Project 1).
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 04 Jan 2016 03:08 |
| Last Modified: | 09 Feb 2016 03:14 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/70 |
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