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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.
- Source :
-
Neurobiology of aging [Neurobiol Aging] 2015 Jun; Vol. 36 (6), pp. 2213-23. Date of Electronic Publication: 2015 Mar 05. - Publication Year :
- 2015
-
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.<br /> (Published by Elsevier Inc.)
- Subjects :
- Aging metabolism
Aging pathology
Animals
Disease Models, Animal
Down-Regulation
Endoplasmic Reticulum physiology
Endoplasmic Reticulum Chaperone BiP
Female
Homeostasis
Humans
Male
Molecular Chaperones
Parkinson Disease genetics
Protein Folding
Rats, Inbred F344
Aging genetics
Dopaminergic Neurons drug effects
Gene Knockdown Techniques
Heat-Shock Proteins genetics
Heat-Shock Proteins physiology
RNA, Small Interfering genetics
Substantia Nigra cytology
alpha-Synuclein toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 1558-1497
- Volume :
- 36
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Neurobiology of aging
- Publication Type :
- Academic Journal
- Accession number :
- 25863526
- Full Text :
- https://doi.org/10.1016/j.neurobiolaging.2015.02.018