Apoptosis accompanied by up-regulation of TNF-α death pathway genes in the brain of Niemann-Pick type C disease

Niemann-Pick disease type C (NP-C) is an autosomal recessive neurovisceral storage disease with neurodegeneration caused by mutations in either the NPC-1 or NPC-2 gene. The murine ortholog of NPC-1 is mutated in BALB/c npcnih and this mutant mouse shows equally conspicuous neurodegeneration and loss of neurons. However, the molecular mechanisms causing neurodegeneration in NP-C remain elusive. Here, we report the presence of apoptotic cells detected by both TUNEL staining and electron microscopy in the cerebrum and cerebellum of human patients and the mouse model. Moreover, we found that with progression of the disease process leading to neuronal cell death, an up-regulation of genes involved in the TNF-α death pathway caspase-8, FADD, TNFRp55, TRADD, and RIP-by an RNA protection assay. Furthermore, RT-PCR showed that TNF-α mRNA expression level also increased up to 30-50-fold in the cerebellum of 7- and 9-week-old NP-C mice compared with wild-type mice. Elevated expression of TNF-α was detected in both neurons and astrocytes with TNF-α-expressing astrocytes distributed in the affected brain regions. Collectively, our results suggest that the cell death in the brain of NP-C disease occurs through apoptosis and it is mediated by the TNF receptor superfamily pathway.