title: Up-regulation of activating transcription factor 4 induces severe loss of dopamine nigral neurons in a rat model of Parkinson's disease.
abstract: Activating transcription factor 4 (ATF4) is a member of the PERK signaling pathway, which directly binds endoplasmic reticulum stress target genes and plays a crucial role in both adaptations to stress and activation of apoptosis. Previous publications demonstrated conflicting evidence on the role of ATF4 in the pathogenesis of neurodegenerative disorders. In this study, we used recombinant adeno-associate virus (rAAV)-mediated gene transfer to investigate if the sustained up-regulation of ATF4 launches a pro-survival or pro-death trend in the dopamine (DA) cells of the substantia nigra pars compacta in a rat model of Parkinson-like neurodegeneration induced by human alpha-synuclein (αS) overexpression. We showed that ATF4 does not protect nigral DA neurons against an αS-induced pathology. Moreover, the rAAV-mediated overexpression of ATF4 resulted in severe nigra-striatal degeneration via activation of caspases 3/7.
authors.affiliation: Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Gully
authors.affiliation: Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Biology, Udmurt State University, Izhevsk, Russia.
authors.forename: Valeriy G
authors.initials: VG
authors.lastname: Sergeyev
authors.affiliation: Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Bhootada
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Hector
authors.initials: H
authors.lastname: Mendez-Gomez
authors.affiliation: Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Meyers
authors.affiliation: Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Zolotukhin
authors.affiliation: Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Marina S
authors.initials: MS
authors.lastname: Gorbatyuk
authors.affiliation: Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Neurology, Center for Neurodegeneration and Experimental Therapy, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: oleggor@uab.edu.
authors.forename: Oleg S
authors.initials: OS
authors.lastname: Gorbatyuk
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D065842:Pars Compacta / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: C497110:Atf4 protein, rat; D051844:alpha-Synuclein; D051701:Activating Transcription Factor 4; D014446:Tyrosine 3-Monooxygenase; C505410:Casp3 protein, rat; D053148:Caspase 3; D053179:Caspase 7
keywords: AAV; ATF4; Alpha-synuclein; ER stress response; Parkinson's disease