title: The loss of glucose-regulated protein 78 (GRP78) during normal aging or from siRNA knockdown augments human alpha-synuclein (α-syn) toxicity to rat nigral neurons.
abstract: Age-related structural changes and gradual loss of key enzymes significantly affect the ability of the endoplasmic reticulum (ER) to facilitate proper protein folding and maintain homeostasis. In this work, we present several lines of evidence supporting the hypothesis that the age-related decline in expression of the ER chaperone glucose-regulated protein 78 (GRP78) could be related to the development of Parkinson's disease. We first determined that old (24 months) rats exhibit significantly lower levels of GRP78 protein in the nigrostriatal system as compared with young (2 months) animals. Then using recombinant adeno-associate virus-mediated gene transfer, we found that GRP78 downregulation by specific small interfering RNAs (siRNAs) aggravates alpha-synuclein (α-syn) neurotoxicity in nigral dopamine (DA) neurons. Moreover, the degree of chaperone decline corresponds with the severity of neurodegeneration. Additionally, comparative analysis of nigral tissues obtained from old and young rats revealed that aging affects the capacity of nigral DA cells to upregulate endogenous GRP78 protein in response to human α-syn neurotoxicity. Finally, we demonstrated that a sustained increase of GRP78 protein over the course of 9 months protected aging nigral DA neurons in the α-syn-induced rat model of Parkinson's-like neurodegeneration. Our data indicate that the ER chaperone GRP78 may have therapeutic potential for preventing and/or slowing age-related neurodegeneration.
authors: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, USA; The Powell Gene Therapy Center, College of Medicine, University of Florida, Gainesville, FL, USA; Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: Maxim
authors: M
authors: Salganik
authors: Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Biology, Udmurt State University, Izhevsk, Russia.
authors: Valeriy G
authors: VG
authors: Sergeyev
authors: Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Vishal
authors: V
authors: Shinde
authors: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors: Craig A
authors: CA
authors: Meyers
authors: Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Marina S
authors: MS
authors: Gorbatyuk
authors: Department of Pathology, University of California, La Jolla, CA, USA.
authors: Jonathan H
authors: JH
authors: Lin
authors: The Powell Gene Therapy Center, College of Medicine, University of Florida, Gainesville, FL, USA; Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA.
authors: Sergey
authors: S
authors: Zolotukhin
authors: 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: Oleg S
authors: OS
authors: Gorbatyuk
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects*; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D055785:Gene Knockdown Techniques; D006360:Heat-Shock Proteins / Q000235:genetics / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D008297:Male; D018832:Molecular Chaperones; D010300:Parkinson Disease / Q000235:genetics; D017510:Protein Folding; D034741:RNA, Small Interfering / Q000235:genetics; D011916:Rats, Inbred F344; D013378:Substantia Nigra / Q000166:cytology*; D051844:alpha-Synuclein / Q000633:toxicity*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C051684:GRP78 protein, rat; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; D051844:alpha-Synuclein
keywords: Dopamine; Glucose regulated protein 78; Parkinson Disease; Recombinant Adeno-associated virus; Substantia nigra pars compacta; Tyrosine hydroxylase