NPC1-deficient neurons are selectively vulnerable for statin treatment.

Niemann Pick C (NPC) is a fatal hereditary neurovisceral disorder associated with a progressive loss of neurons of unknown mechanism. The disease is caused by mutation in either of two genes, termed npc1 and npc2, accounting for ∼95% and ∼5% of patients, respectively. Recent data suggest a cell-autonomous cause for neuronal cell death. In a former study we could demonstrate that cultured NPC1-deficient (NPC1-/-) neurons are more susceptible to autophagic stress than NPC1-wildtype (wt) neurons. In the present study we tested other stressors for a selective effect on the survival of NPC1-/- neurons. To that end we challenged cultured primary cortical neurons from a NPC mouse model and from wild type littermate mice by a variety of different stressors: glutamate, hydrogen superoxide, osmotic shock and inhibition of HMG-CoA reductase. In all paradigms neurons behave virtually identical with one exception: NPC1 deficient neurons are more vulnerable against a challenge with lovastatin. The analysis of the molecular background provides evidence that statin endangers survival of neurons by interfering in the autophagy of cells.

Detection of antibodies against adenovirus protein IX, fiber, and hexon in human sera by immunoblot assay.

The 51 serotypes of human adenoviruses (HAdVs) of the genus Mastadenovirus are classified into the six species HAdV-A to HAdV-F. For the detection of genus- and species-specific antibodies in human sera an immunoblot assay was developed. The recombinant long fiber of HAdV-41[F] (Ad41Fi) and the native hexon of HAdV-5[C] were used as genus-specific antigens. The recombinant capsid protein IX (pIX) of HAdV-2 (Ad2pIX[C]) and HAdV-41 (Ad41pIX[F]), the C-terminal pIX part of HAdV-3 (Ad3pIXC[B]), and the fiber knob of HAdV-8 (Ad8FiKn[D]) were evaluated as representative species-specific antigens. Hence, the pIX amino acid sequences of numerous serotypes of all HAdV species were compared, and the cross-reactivities of pIX antigens with rabbit hyperimmune sera among HAdV-A to -F were analyzed. In an epidemiological study, 667 human patient sera, not selected for viral infection, were screened for adenovirus seroprevalence. The genus-specific antibody prevalences directed against the Ad41Fi and HAdV-5 hexon were 82.8 and 98.8%, respectively. The species-specific antibody prevalence of 44.7% against Ad2pIX[C], 36.6% against Ad41pIX[F], 26.4% against Ad8FiKn[D], and 18% against Ad3pIXC[B] showed an age-dependent distribution and correlated well with the frequency of isolated serotypes of the respective species in earlier studies (except HAdV-D). In conclusion, the immunoblot assay using pIX, fiber, and hexon antigens represents a valuable and new serological tool for refined adenovirus diagnosis as shown in an epidemiological study.