title: Sodium benzoate, a metabolite of cinnamon and a food additive, upregulates neuroprotective Parkinson disease protein DJ-1 in astrocytes and neurons.
abstract: DJ-1 (PARK7) is a neuroprotective protein that protects cells from oxidative stress. Accordingly, loss-of-function DJ-1 mutations have been linked with a familial form of early onset Parkinson disease. Mechanisms by which DJ-1 level could be enriched in the CNS are poorly understood. Recently we have discovered anti-inflammatory activity of sodium benzoate (NaB), a metabolite of cinnamon and a widely-used food additive. Here we delineate that NaB is also capable of increasing the level of DJ-1 in primary mouse and human astrocytes and human neurons highlighting another novel neuroprotective effect of this compound. Reversal of DJ-1-inducing effect of NaB by mevalonate, farnesyl phosphate, but not cholesterol and ubiquinone, suggests that depletion of intermediates, but not end products, of the mevalonate pathway is involved in the induction of DJ-1 by NaB. Accordingly, either an inhibitor of p21(ras) farnesyl protein transferase (FPTI) or a dominant-negative mutant of p21(ras) alone was also able to increase the expression of DJ-1 in astrocytes suggesting an involvement of p21(ras) in DJ-1 expression. However, an inhibitor of geranyl geranyl transferase (GGTI) and a dominant-negative mutant of p21(rac) had no effect on the expression of DJ-1, indicating the specificity of the effect. Similarly lipopolysaccharide (LPS), an activator of small G proteins, also inhibited the expression of DJ-1, and NaB and FPTI, but not GGTI, abrogated LPS-mediated inhibition. Together, these results suggest that NaB upregulates DJ-1 via modulation of mevalonate metabolites and that p21(ras), but not p21(rac), is involved in the regulation of DJ-1.
authors.affiliation: Department of Neurological Sciences, Division of Neuroscience, Rush University Medical Center, 1735 West Harrison Street, Chicago, IL 60612, USA.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Khasnavis
authors.forename: Kalipada
authors.initials: K
authors.lastname: Pahan
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002935:Cinnamomum zeylanicum / Q000378:metabolism; D005503:Food Additives / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015513:Oncogene Proteins / Q000096:biosynthesis*; D010300:Parkinson Disease / Q000378:metabolism; D000071617:Protein Deglycase DJ-1; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D020160:Sodium Benzoate / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D005503:Food Additives; D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D015513:Oncogene Proteins; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D020160:Sodium Benzoate; D008798:Mevalonic Acid