PrP C -deficient mice expressing prion protein variants with large amino-proximal deletions (termed PrP DF ) suffer from neurodegeneration, which is rescued by full-length PrP C . We now report that expression of PrP DCD , a PrP variant lacking 40 central residues (94-134), induces a rapidly progressive, lethal phenotype with extensive central and peripheral myelin degeneration. This phenotype was rescued dose-dependently by coexpression of full-length PrP C or PrP C lacking all octarepeats. Expression of a PrP C variant lacking eight residues (114-121) was innocuous in the presence or absence of full-length PrP C , yet enhanced the toxicity of PrP DCD and diminished that of PrP DF . Therefore, deletion of the entire central domain generates a strong recessive-negative mutant of PrP C , whereas removal of residues 114-121 creates a partial agonist with context-dependent action. These findings suggest that myelin integrity is maintained by a constitutively active neurotrophic protein complex involving PrP C , whose effector domain encompasses residues 94-134.

Inhibition of the small GTPase Rho or of its downstream target Rho-associated kinase (ROCK) has been shown to promote axon regeneration and to improve functional recovery following traumatic CNS lesions in the adult rat. In order to determine the expression pattern of RhoA and RhoB following human traumatic brain injury (TBI) and to assess whether Rho is a possible target for pharmacological intervention in humans, we investigated expression patterns of RhoA and RhoB in brain specimens from 25 patients who died after closed TBI in comparison to brain tissue derived from four neuropathologically unaffected control patients by immunohistochemistry. A highly significant lesional upregulation of both RhoA and RhoB was observed beginning several hours after the traumatic event and continuing for months after TBI. The cellular sources of both molecules included polymorphonuclear granulocytes, monocytes/macrophages, and reactive astrocytes. Additionally, expression of RhoA was also detected in neuronal cells in some of the cases. From our data, we conclude that inhibition of Rho is a promising mechanism for the development of new pharmacological interventions in human TBI. As the observed upregulation of RhoA and RhoB was still detectable months after TBI, we speculate that even delayed treatment with Rho inhibitors might be a therapeutic option.

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Inhibition of Rho is a promising lead for the development of new pharmacologic interventions in FCI. Because the observed up-regulation of RhoA and RhoB was still detectable months after FCI, we speculate that even delayed treatment with Rho inhibitors might be a therapeutic option.

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DNA strand breaks induced by alkylating agents, oxidants, or ionizing radiation trigger the covalent modification of nuclear proteins with poly(ADP-ribose), which is catalyzed for the most part by poly(ADP-ribose) polymerase-1 and plays a role in DNA base-excision repair. Poly(ADP-ribosyl)ation capacity of mononuclear blood cells correlates positively with life span of mammalian species. Here, we show that L-selegiline, an anti-Parkinson drug with neuroprotective activity and life span-extending effect in laboratory animals, can potentiate ␥-radiation-induced poly(ADP-ribose) formation in intact cells. COR4 hamster cells were incubated with L-selegiline (50 nM) for various time periods, followed by ␥-irradiation (45 Gy). Quantification of cellular poly(ADP-ribose) levels at 10 min after starting the irradiation revealed significant increases (up to 1.8-fold) in cells preincubated with the drug for 8 h to 7 days compared with drug-free irradiated controls. There was no selegiline-induced change in poly(ADP-ribose) levels of unirradiated cells nor in basal or radiation-induced DNA strand breaks, respectively. Surprisingly, poly(ADP-ribose) polymerase-1 protein was down-regulated by L-selegiline treatment. Addition of L-selegiline to purified poly(ADP-ribose) polymerase-1 did not alter enzymatic activity. In conclusion, the results of the present study identify a novel intervention to potentiate the cellular poly(ADP-ribosyl)-ation response. We hypothesize that the effect of L-selegiline is due to modulation of accessory proteins regulating poly(ADPribose) polymerase-1 activity and that increased cellular poly-(ADP-ribosyl)ation capacity may contribute to the neuroprotective potential and/or life span extension afforded by L-selegiline.