Serotonergic (5-HT) neurons degenerate in Parkinson's disease. To determine the role of this 5-HT injury-besides the dopaminergic one in the parkinsonian symptomatology-we developed a new monkey model exhibiting a double dopaminergic/serotonergic lesion by sequentially using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3,4-methylenedioxy-N-methamphetamine (MDMA, better known as ecstasy). By positron emission tomography imaging and immunohistochemistry, we demonstrated that MDMA injured 5-HT nerve terminals in the brain of MPTP monkeys. Unexpectedly, this injury had no impact on tremor or on bradykinesia, but altered rigidity. It abolished the l-DOPA-induced dyskinesia and neuropsychiatric-like behaviours, without altering the anti-parkinsonian response. These data demonstrate that 5-HT fibres play a critical role in the expression of both motor and non-motor symptoms in Parkinson's disease, and highlight that an imbalance between the 5-HT and dopaminergic innervating systems is involved in specific basal ganglia territories for different symptoms.

SummarySporulation in Bacillus subtilis is a primitive differentiation process involving two cell types, the forespore and the mother cell. Each cell implements two successive transcription programmes controlled by specific sigma factors. We report that activity of s G , the late forespore sigma factor, is kept in check by Gin, the product of csfB, a gene controlled by s F , the early forespore sigma factor. Gin abolishes s G transcriptional activity when s G is artificially synthesized during growth, but has no effect on s F . Gin interacts strongly with s G but not with s F in a yeast two-hybrid experiment. The absence of Gin allows s G to be active during sporulation independently of the mother-cell development to which it is normally coupled. Premature s G activity leads to the formation of slowgerminating spores, and complete deregulation of s G synthesis is lethal when combined with gin inactivation. Gin allows s F to delay the switch to the late forespore transcription programme by preventing s G to take over before the cell has reached a critical stage of development. A similar strategy, following a completely unrelated route, is used by the mother cell.

The atypical hemolytic Listeria innocua strains PRL/NW 15B95 and J1-023 were previously shown to contain gene clusters analogous to the pathogenicity island (LIPI-1) present in the related foodborne gram-positive facultative intracellular pathogen Listeria monocytogenes, which causes listeriosis. LIPI-1 includes the hemolysin gene, thus explaining the hemolytic activity of the atypical L. innocua strains. No other L. monocytogenesspecific virulence genes were found to be present. In order to investigate whether any other specific L. monocytogenes genes could be identified, a global approach using a Listeria biodiversity DNA array was applied. According to the hybridization results, the isolates were defined as L. innocua strains containing LIPI-1. Surprisingly, evidence for the presence of the L. monocytogenes-specific inlA gene, previously thought to be absent, was obtained. The inlA gene codes for the InlA protein which enables bacterial entry into some nonprofessional phagocytic cells. PCR and sequence analysis of this region revealed that the flanking genes of the inlA gene at the upstream, 5-end region were similar to genes found in L. monocytogenes serotype 4b isolates, whereas the organization of the downstream, 3-end region was similar to that typical of L. innocua. Sequencing of the inlA region identified a small stretch reminiscent of the inlB gene of L. monocytogenes. The presence of two clusters of L. monocytogenes-specific genes makes it unlikely that PRL/NW 15B95 and J1-023 are L. innocua strains altered by horizontal transfer. It is more likely that they are distinct relics of the evolution of L. innocua from an ancestral L. monocytogenes, as postulated by others.Listeria innocua is a species that is ubiquitously distributed in the natural environment, and unlike L. monocytogenes, represents an example of a nonharmful, nonhemolytic saprophytic Listeria sp. L. innocua has been isolated from a variety of environmental sources, including surface water, soil, sewage, vegetation, and food-processing plants. According to current knowledge, L. innocua does not carry the virulence-associated genes or clusters present and described in the genomes of the pathogenic Listeria species, L. monocytogenes and L. ivanovii. However, several unusual L. monocytogenes-like hemolytic L. innocua strains were isolated and phenotypically and genetically characterized (19). An example is the food isolate PRL/NW 15B95, a naturally but atypically hemolytic L. innocua strain (19). We have shown previously that this L. innocua strain contains the L. monocytogenes PrfA-regulated pathogenicity island 1 (LIPI-1) gene cluster. LIPI-1 of strain PRL/NW 15B95 is inserted in a background in which L. innocua genes preponderate. The initial characterization of this strain did not allow a definitive conclusion about how it evolved, although the results indicated horizontal transfer of this island, as other, non-LIPI-1 genes of L. monocytogenes were absent. Thus, importation of the cluster into an ancestral L. innocua strain rather than v...

It is now widely accepted that compensatory mechanisms are involved during the early phase of Parkinson's disease (PD) to delay the expression of motor symptoms. However, the neurochemical mechanisms underlying this presymptomatic period are still unclear. Here, we measured in vivo longitudinal changes of both the dopaminergic and serotonergic systems in seven asymptomatic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated monkeys (when motor symptoms are less apparent) using PET. We used the progressively MPTP-intoxicated monkey model that expresses recovery from motor symptoms to study the changes in dopamine synthesis ([ Significance StatementThe present research provides evidence of the potential of combining a multitracer PET imaging technique and a longitudinal protocol applied on a progressively 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated monkey model to further elucidate the nature of the compensatory mechanisms involved in the preclinical period of Parkinson's disease (PD). In particular, by investigating the dopaminergic and serotonergic changes both presynaptically and postsynaptically at four different motor states (baseline, early symptomatic, full symptomatic, and recovered), this study has allowed us to identify putative biomarkers for future therapeutic interventions to prevent and/or delay disease expression. For example, our findings suggest that the external pallidum could be a new target for cell-based therapies to reduce PD symptoms.

Endospore formation is a characteristic shared by some Bacilli and Clostridia that involves the creation of two cell types, the forespore and the mother cell. Hundreds of protein-encoding genes have been shown to be transcribed in a cell-specific fashion during this developmental process in Bacillus subtilis. We have used a phylogenetic profiling procedure to identify clusters of B. subtilis coding and non-coding sequences that co-occur in other endospore formers. One such cluster shows a strong bias for sporulation-related genes (42% among 156 genes) and is enriched in potential non-coding RNAs. We have studied one RNA candidate, encoded in the ylbG-ylbH interval. In vivo analysis using a transcriptional fusion to the Escherichia coli lacZ gene demonstrates that this region of the chromosome contains a gene, csfG, encoding a 147-nucleotide RNA that is transcribed only during sporulation, specifically in the forespore. csfG is present in many endospore formers, mostly Bacilli and some Clostridia, whereas it is absent from bacteria that do not produce endospores. All CsfG RNAs contain a strongly conserved, pyrimidine-rich, central motif that overlaps a potential stem-loop structure. The remarkable conservation of this sequence in widely divergent bacteria suggests that it plays a conserved physiological role, presumably by interacting with an unidentified target in the forespore, where it contributes to the acquisition of the spore properties.

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