Mice overexpressing mutant alpha-synuclein develop a progressive loss of motor function associated with the accumulation of aggregated alpha-synuclein in neurons of the brainstem. Recent reports suggest that tau pathology might also be associated with Parkinson disease (PD) and aggregation of alpha-synuclein. We now report that mice overexpressing A30P alpha-synuclein develop abnormally phosphorylated tau in parallel with the accumulation of aggregated alpha-synuclein. Enhanced phosphorylation of tau occurs only in symptomatic mice that also harbor abundant aggregated alpha-synuclein. The increased phosphorylation of tau occurs at S396/404 and S202 as shown by immunoblotting and immunocytochemical studies with the antibodies PHF-1 and AT8. Neurons that accumulated alpha-synuclein occurred in the dorsal brainstem and did not show strong colocalization with neurons that showed abnormal tau phosphorylation, which largely occurred in the ventral brainstem. Aggregation of alpha-synuclein and phosphorylation of tau are associated with increased levels of phosphorylated c-jun kinase (JNK), which is a stress kinase known to phosphorylate tau protein. These results suggest that alpha-synuclein pathology can stimulate early pathological changes in tau.

Systemic lupus erythematosus (SLE) is characterized by a variety of autoantibodies and other immune abnormalities indicative of an immunological hyperactivity. Antibodies against native DNA, however, are a disease-specific marker and play a major role in the pathogenesis of systemic or organ-specific disease manifestations. Nevertheless, the mechanisms causing the appearance of autoantibodies and immune complexes in SLE are not yet understood. Here, we report that chromosomal DNA and other forms of nucleic acids are usually cleared from circulation by binding to a yet unidentified receptor-like protein on the surface membrane of erythrocytes, independently from complement or antibodies. The binding kinetics of DNA and other nucleic acids to erythrocytes are significantly altered in SLE patients, showing an overall reduced binding capability and presaturated binding kinetics. Significant amounts of chromosomal DNA can be isolated from erythrocytes of SLE patients but not from normal controls. Electron microscopy shows electron-dense particles on the surface of SLE erythrocytes (approximate size 20–40 nm). Comparative genomic hybridization reveals that the nucleic acid isolated from erythrocytes of SLE patients is of genomic and random origin, leading to an accumulation of ”free” nucleic acids in the periphery, which eventually induces a B-cell immune response.

This immunohistochemical and molecular morphological study on the so called Kaposi's sarcoma (KS, n = 41) considers the conflicting hypotheses whether the KS is a pure angioproliferative process like granulation tissue or whether it has a true malignant nature, which would justify its classification as angiosarcoma. We compared early angiomatoid and late sarcomatoid KS lesions (KS-A/KS-S) with granulation tissue (GT, n = 47) and 'classical' angiosarcoma. (AS, n = 19) investigating the important cell cycle and apoptosis control proteins p53, mdm2, p21(WAF-1) and bcl-2. The results show a continuously increasing percentage of positive immunohistochemical results from GT to KS and AS. RNA in situ hybridization on early and late KS lesions (n = 10) for the recently described KS associated human herpesvirus 8 (HHV-8) exhibited a minor cell population of HHV-8 infected macrophages in KS-A compared to a widespread expression of HHV-8 Kaposin gene in spindle cells of KS-S.Immunohistological results and the different expression of HHV-8 gens suggest a switch on the pathogenetic pathway at the morphological transition from KS-A to KS-S. Based on former studies of our group the hypothesis is discussed that the early KS stage is trigged by a HIV-associated vasculopathy with an increased monocyte adhesion. This initiates an angioproliferation by para- and autocrine mechanisms. The activated and proliferating endothelial cells in the early KS provide excellent conditions for replication of HHV-8 which induces the switch to the spindle cell morphology in the late KS.

The endothelium is one of the largest cellular compartments of the human body and has a high proliferative potential. However, angiosarcomas are among the rarest malignancies. Despite this interesting contradiction, data on growth and angiogenesis control mechanisms of angiosarcomas are scarce. In this study of 19 angiosarcomas and 10 benign vascular control lesions we investigated the sequence and expression of the p53 tumor suppressor gene and the expression of the mdm-2 proto-oncogene, which is a negative regulator of p53 activity and of the vascular endothelial growth factor (VEGF), whose expression, among other factors, is regulated by the p53/MDM-2 pathway. Ten sarcomas (53%) exhibited clear nuclear p53 protein accumulation. Two of these cases revealed mutations in the sequence-specific DNA binding domain of the p53 gene. Thirteen angiosarcomas (68%) showed an increased amount of MDM-2 protein. Elevated expression of p53 and MDM-2 protein correlated with increased VEGF expression, which was found in nearly 80% of the angiosarcoma cases. Negative or clearly lower immunostaining was obtained in cases from the benign control collective. Only one case of a juvenile hemangioma reached the cutoff value of p53 positivity coincidentally with high VEGF expression, Our data suggest that the p53/MDM-2 pathway is impaired in about two-thirds (14/19) of the angiosarcomas, This may be a key event in the pathogenesis of human angiosarcomas, The increased VEGF expression observed supports this hypothesis.