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- Title
Phosphorylation of Huntingtin at Ser<sup>421</sup> in YAC128 Neurons Is Associated with Protection of YAC 128 Neurons from NMDA-Mediated Excitotoxicity and Is Modulated by PP1 and PP2A.
- Authors
Metzler, Martina; Gan, Lu; Mazarei, Gelareh; Graham, Rona K.; Liu, Lili; Bissada, Nagat; Lu, Ge; Leavitt, Blair R.; Hayden, Michael R.
- Abstract
YAC transgenic mice expressing poly(Q)-expanded full-length huntingtin (mhtt) recapitulate many behavioral and neuropathological features of Huntington disease (HD). We have previously observed a reduction in phosphorylation of mhtt at S421 in the presence of the mutation for HD. In addition, phosphorylation of normal S421-htt is reduced after excitotoxic stimulation of NMDA receptors (NMDARs). To test whether NMDAR stimulation contributes to reduced pS42 1-htt levels in HD, we determined phosphorylation of htt at Ser42' after NMDA-induced excitotoxicity in neurons from YAC128 mice. Here, we report that the total level of pS421 -htt is reduced in YAC 128 primary neurons after excitotoxic NMDAR stimulation. Similarly, the total level of pS421-htt is reduced in YAC128 transgenic mice after quinolinic acid injection into the striatum. In contrast, loss of phosphorylation of pS421-htt is prevented in YAC mice that never develop clinical or neuropathological features of HD [the caspase 6-resistant YAC 128 transgene (C6R)]. To gain insight into the mechanisms underlying these findings, we determined that the Ser/Thr protein phosphatases PP 1 and PP2A dephosphorylate p5421 -htt in situ and after excitotoxic stimulation of NMDARs in neurons. Furthermore, increasing the phosphoryla- tion of htt at S421 by blocking PP1 and PP2A activity protects YAC 128 striatal neurons from NMDA-induced cell death. These results, together with the observed modulation ofpS42 1 -htt levels by dopamine, the reduced expression of PP 1 inhibitor Darpp-32 in the striatum of YAC 128 mice, and the reduced phosphorylation of PP1 substrate CreB, point to altered regulation of phosphatase activity in HD and highlight enhancing phosphorylation of htt at S421 as a therapeutic target.
- Subjects
HUNTINGTON disease; PHOSPHORYLATION; NEURONS; METHYL aspartate; TRANSGENIC mice; PHOSPHATASES
- Publication
Journal of Neuroscience, 2010, Vol 30, Issue 43, p14318
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.1589-10.2010