ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin

Xiaotian Sun, Jin Liu, John F. Crary, Cristina Malagelada, David Sulzer, Lloyd A. Greene, Oren A. Levy

Research output: Contribution to journalArticlepeer-review

110 Scopus citations

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder, for which there are no effective disease-modifying therapies. The transcription factor ATF4 (activating transcription factor 4) is induced by multiple PD-relevant stressors, such as endoplasmic reticulum stress and oxidative damage. ATF4 may exert either protective or deleterious effects on cell survival, depending on the paradigm. However, the role of ATF4 in the pathogenesis of PD has not been explored. We find that ATF4 levels are increased in neuromelanin positive neurons in the substantia nigra of a subset of PD patients relative to controls. ATF4 levels are also up regulated in neuronal PC12 cells treated with the dopaminergic neuronal toxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+). To explore the role of ATF4 in cell survival in PD-relevant contexts, we either silenced or over expressed ATF4 in cellular models of PD. In neuronal PC12 cells, silencing of ATF4 enhanced cell death in response to either 6-OHDA or MPP+. Conversely, over expression of ATF4 reduced cell death caused by dopaminergic neuronal toxins. ATF4 was also protective against 6-OHDA-induced death of cultured mouse ventral midbrain dopaminergic neurons. We further show that parkin, a gene associated with autosomal recessive PD, plays a critical role in ATF4-mediated protection. After treatment with 6-OHDA or MPP+, parkin protein levels fall, despite an increase in mRNA levels. ATF4 silencing exacerbates the toxin-induced reduction of parkin, whereas ATF4 over expression partially preserves parkin levels. Finally, parkin silencing blocked the protective capacity of ATF4. These results indicate that ATF4 plays a protective role in PD through the regulation of parkin.

Original languageEnglish
Pages (from-to)2398-2407
Number of pages10
JournalJournal of Neuroscience
Volume33
Issue number6
DOIs
StatePublished - 6 Feb 2013
Externally publishedYes

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