title: ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin.
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 upregulated 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 overexpressed 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, overexpression 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 overexpression 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.
authors: Department of Pathology, Columbia University Medical Center, New York, New York 10032, USA.
authors: Xiaotian
authors: X
authors: Sun
authors: Jin
authors: J
authors: Liu
authors: John F
authors: JF
authors: Crary
authors: Cristina
authors: C
authors: Malagelada
authors: David
authors: D
authors: Sulzer
authors: Lloyd A
authors: LA
authors: Greene
authors: Oren A
authors: OA
authors: Levy
mesh_terms: D051701:Activating Transcription Factor 4 / Q000096:biosynthesis* / Q000502:physiology; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism*; D016716:PC12 Cells; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
chemical_list: C497109:ATF4 protein, human; D018696:Neuroprotective Agents; D051701:Activating Transcription Factor 4; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
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