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
| Autor: | Salganik, M, Sergeyev, VG, Shinde, V, Meyers, CA, Gorbatyuk, MS, Lin, JH, Zolotukhin, S, Gorbatyuk, OS |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Protein Folding Aging Dopamine Clinical Sciences Down-Regulation Endoplasmic Reticulum Small Interfering Animals Humans Homeostasis Heat-Shock Proteins Inbred F344 Neurology & Neurosurgery Animal Dopaminergic Neurons Neurosciences Parkinson Disease nervous system diseases Rats Substantia nigra pars compacta Substantia Nigra Glucose regulated protein 78 nervous system Gene Knockdown Techniques Disease Models alpha-Synuclein RNA Female Recombinant Adeno-associated virus Tyrosine hydroxylase Molecular Chaperones |
| Zdroj: | Neurobiology of aging, vol 36, iss 6 Salganik, M; Sergeyev, VG; Shinde, V; Meyers, CA; Gorbatyuk, MS; Lin, JH; et al.(2015). 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. Neurobiology of Aging, 36(6), 2213-2223. doi: 10.1016/j.neurobiolaging.2015.02.018. UC San Diego: Retrieved from: http://www.escholarship.org/uc/item/2xv2w48q |
| DOI: | 10.1016/j.neurobiolaging.2015.02.018. |
| Popis: | 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 GRP78 (GRP78) could be related to the development of Parkinson’s disease (PD). We first determined that old (24 month) rats exhibit significantly lower levels of GRP78 protein in the nigrastriatal system as compared to young (2 month) animals. Then using recombinant adeno-associate virus (rAAV) mediated gene transfer, we found that GRP78 down-regulation 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 nine 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. |
| Databáze: | OpenAIRE |
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