Necroptosis in Niemann-Pick disease, type C1: a potential therapeutic target.

Niemann-Pick disease, type C1 (NPC1) is a neurodegenerative, lysosomal storage disorder due to mutation of the NPC1 gene. The NPC1 phenotype is characterized by progressive neuronal dysfunction, including cerebellar ataxia and dementia. There is histological evidence of neuroinflammation and progressive neuronal loss, with cerebellar Purkinje cells particularly vulnerable to loss of NPC1 function. Necroptosis was evaluated as a mechanism of neuronal loss. Receptor-interacting protein kinase 1 (RIP1) and RIP3 are key components of the necrosomal complex that regulates necroptotic cell death. We report increased expression of RIP1 and RIP3 in NPC1 fibroblasts, NPC1 iPS cell-derived neuronal precursors, and in cerebellar tissue from both NPC1 mice and patients. Our data suggest a positive correlation between NPC1 neurological disease severity and assembly of the necrosome complex. Furthermore, we demonstrate that pharmacological inhibition of RIP1 decreases cell death both in vitro and in vivo. Treatment of Npc1-mutant mice with necrostatin-1, an allosteric inhibitor of RIP1, significantly delayed cerebellar Purkinje cell loss, progression of neurological symptoms, and death. Collectively, our data identified necroptosis as a key component of the molecular network that contributes to neuronal loss in NPC1 and establish that inhibition of necroptosis is a potential therapeutic intervention.

Conservation and function of a bovine sperm A-kinase anchor protein homologous to mouse AKAP82.

Protein kinase A regulates sperm motility through the cAMP-dependent phosphorylation of proteins. One mechanism to direct the activity of the kinase is to localize it near its protein substrates through the use of anchoring proteins. A-Kinase anchoring proteins (AKAPs) act by binding the type II regulatory subunit of protein kinase A and tethering it to a cellular organelle or cytoskeletal element. We showed previously that mAKAP82, the major protein of the fibrous sheath of the mouse sperm flagellum, is an AKAP. The available evidence indicates that protein kinase A is compartmentalized to the fibrous sheath by binding mAKAP82. To characterize AKAP82 in bovine sperm, a testicular cDNA library was constructed and used to isolate a clone encoding bAKAP82, the bovine homologue. Sequence analysis showed that the primary structure of bAKAP82 was highly conserved. In particular, the amino acid sequence corresponding to the region of mAKAP82 responsible for binding the regulatory subunit of protein kinase A was identical in the bull. Bovine AKAP82 was present in both epididymal and ejaculated sperm and was localized to the entire principal piece of the flagellum, the region in which the fibrous sheath is located. Finally, bAKAP82 bound the regulatory subunit of protein kinase A. These data support the idea that bAKAP82 functions as an anchoring protein for the subcellular localization of protein kinase A in the flagellum.

[Plasma concentration and elimination behavior of the cardiac glycoside meproscillarin in patients with liver cirrhosis]. / Plasmakonzentration und Eliminationsverhalten des Herzglykosids Meproscillarin bei Patienten mit Leberzirrhose.

During a one week period patients with liver cirrhosis and a control group were treated with a repeated dosage of the new heart glcoside Meproscillarin. After achieving a steady state in plasma level the same Meproscillarin plasma levels were found among both groups. Compared with the control group no difference was detected in the elimination rate of Meproscillarin in patients with liver cirrhosis, which means a complex disturbed liver function. Nevertheless the greater variance of the Meproscillarin plasma levels in the patients with liver cirrhosis in comparison with the controls means a diminished predictability of the therapeutic success in the cirrhosis group. With this limitation Meproscillarin can be used therapeutically in patients with liver cirrhosis, because a toxic accumulation is not to be expected.

[Esophageal stenosis in sjögren's syndrome]. / Osophagusstenose bei Sjögren-Syndrom.

Dysphagia in Sjögren's syndrome may be caused by xerostomy, pharyngoesophagitis and esophageal membranes. This is the first report on a tubular upper esophageal stenosis in a 71 year old woman with Sjögren's syndrome who developed progressive dysphagia. It is suggested, that this stenosis was due to chronic inflammatory processes and secondary sclerosis of deep layers in the esophageal wall. Bouginage was adequate symptomatic therapy. Tubular esophageal stenosis is regarded as gastrointestinal manifestation of Sjögren's syndrome.