[Show abstract][Hide abstract] ABSTRACT: Prion propagation involves conversion of host PrP(C) to a disease-related isoform, PrP(Sc), which accumulates during disease and is the principal component of the transmissible agent. Proteolysis seems to play an important role in PrP metabolism. Plasminogen, a serine protease precursor, has been shown to interact with PrP(Sc). Plasminogen can be proteolytically activated by tissue plasminogen activator (tPA). Recent reports imply a crosstalk between tPA-mediated plasmin activation and PrP. In our study, both tPA activity and tPA gene expression were found elevated in TSE-infected brains as compared to their normal counterparts. Furthermore, it was proved that PrP(Sc), in contrast to PrP(C), could not be degraded by plasmin. In addition, it was observed that TSE symptoms and subsequent death of plasminogen-deficient and tPA-deficient scrapie challenged mice preceded that of wild-type controls. Our data imply that enhanced tPA activity observed in prion infected brains may reflect a neuro-protective response.
Neurobiology of Disease 12/2005; 20(2):519-27. · 5.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tissue plasminogen activator (tPA) may play a deleterious role after brain injury. Here, we compared the response to traumatic brain injury in tPA knockout (KO) and wildtype (WT) mice after controlled cortical impact. At 6 h after trauma, blood-brain barrier permeability was equally increased in all mice. However, by 24 h specific gravity measurements of brain edema were significantly worse in WT mice than in KO mice. At 1 and 2 days post-trauma, mice showed deficits in rotarod performance, but by day 7 all mice recovered motor function and there were no differences between WT and KO mice. At 7 days, cortical lesion volumes were significantly reduced in KO mice compared with WT mice. However, there were no significant differences in CA3 hippocampal neuron survival. These data suggest that tPA amplifies cortical brain damage and edema in this mouse model of traumatic brain injury.
[Show abstract][Hide abstract] ABSTRACT: Short seizure episodes are associated with remodeling of neuronal connections. One region where such reorganization occurs is the hippocampus, and in particular, the mossy fiber pathway. Using genetic and pharmacological approaches, we show here a critical role in vivo for tissue plasminogen activator (tPA), an extracellular protease that converts plasminogen to plasmin, to induce mossy fiber sprouting. We identify DSD-1-PG/phosphacan, an extracellular matrix component associated with neurite reorganization, as a physiological target of plasmin. Mice lacking tPA displayed decreased mossy fiber outgrowth and an aberrant band at the border of the supragranular region of the dentate gyrus that coincides with the deposition of unprocessed DSD-1-PG/phosphacan and excessive Timm-positive, mossy fiber termini. Plasminogen-deficient mice also exhibit the laminar band and DSD- 1-PG/phosphacan deposition, but mossy fiber outgrowth through the supragranular region is normal. These results demonstrate that tPA functions acutely, both through and independently of plasmin, to mediate mossy fiber reorganization.
The Journal of Cell Biology 04/2000; 148(6):1295-304. · 10.82 Impact Factor