Nocardia otitidiscaviarum (GAM-5) induces parkinsonian-like alterations in mouse

Abstract

Parkinson's disease, a major neurodegenerative disorder in humans whose etiology is unknown, may be associated with some environmental factors. Nocardia otitidiscaviarum (GAM-5) isolated from a patient with an actinomycetoma produced signs similar to Parkinson's disease following iv injection into NMRI mice. NMRI mice were infected intravenously with a non-lethal dose of 5 x 10 6 colony forming units of N. otitidiscaviarum (GAM-5). Fourteen days after bacterial infection, most of the 60 mice injected exhibited parkinsonian features characterized by vertical head tremor, akinesia/bradykinesia, flexed posture and postural instability. There was a peak of nocardial growth in the brain during the first 24 h followed by a decrease, so that by 14 days nocardiae could no longer be cultured. At 24 h after infection, Gram staining showed nocardiae in neurons in the substantia nigra and occasionally in the brain parenchyma in the frontal and parietal cortex. At 21 days post-infection, tyrosine hydroxylase immunolabeling showed a 58% reduction of tyrosine hydroxylase in the substantia nigra, and a 35% reduction of tyrosine hydroxylase in the ventral tegmental region. Dopamine levels were reduced from 110 ± 32.5 to 58 ± 16.5 ng/mg protein (47.2% reduction) in brain from infected mice exhibiting impaired movements, whereas serotonin levels were unchanged (191 ± 44 protein in control and 175 ± 39 ng/mg protein in injected mice). At later times, intraneuronal inclusion bodies were observed in the substantia nigra. Our observations emphasize the need for further studies of the potential association between Parkinson's disease or parkinsonism-like disease and exposure to various nocardial species. Correspondence

Nocardia asteroides strain GUH-2 induces proteasome inhibition and apoptotic death of cultured cells

“…Infection of animals with members of the bacterial order Actinomycetales had been found to induce a Parkinsonian syndrome [13,28]. Separately, McNaught et al found that systemic administration of proteasome inhibitors produced by these bacteria to rats could cause Parkinsonism [32].…”

“…The formation of these structures has been linked to inhibition of the ubiquitin-proteasome system [2,7,36]. Similar intraneuronal inclusions have been observed within the brains of mice or monkeys infected with neuroinvasive nocardiae [8,13,28]. Furthermore, in experiments utilizing nocardial culture filtrates to induce dopamine depletion and apoptosis of PC12 cells, Loeffler et al localized the activity within the sub-3-kDa fraction [30].…”

“…Epoxomicin, one of the inhibitors used, is naturally produced by a soil-dwelling aerobic actinomycete [21]. N. asteroides GUH-2 and related bacteria have also been found to induce Parkinsonism in mice, following intravenous administration [13,28]. In both Parkinson's disease and Lewy body dementia, there is an accumulation of ubiquinated protein and alpha synuclein fibrils that form intraneuronal inclusions known as Lewy bodies [17].…”

Widespread Abundance of Functional Bacterial Amyloid in Mycolata and Other Gram-Positive Bacteria

“…Our recent in situ studies using WO2 antibodies specific for the amyloid conformation (36) in conjunction with 16S rRNA-targeted oligonucleotide probes for identification of the microbes revealed that amyloid-like adhesins are widespread in many phyla in environmental biofilms (29). In view of the occurrence of potential amyloid-like fibrils in one species belonging to the mycolata and the observed link between infection by a mycolata genus (Nocardia) and neurodegenerative Parkinson's disease (13,25,26,47), we have investigated this group of bacteria more closely for the presence of amyloid. Here we show that 12 of 14 different species of mycolata, as well as 6 of 6 other gram-positive bacteria, harbor amyloid.…”

Direct Detection of Nocardia spp. in Clinical Samples by a Rapid Molecular Method

“…Recent data suggest that such forms of Nocardia spp. could be implicated in symptoms similar to those of Parkinson's disease (8,10,26). It is necessary to develop methods capable of detecting these Nocardia spp.…”