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.

Mutations in EDARADD account for a small proportion of hypohidrotic ectodermal dysplasia cases.

BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of the eccrine sweat glands, hair and teeth. The X-linked form of the disease, caused by mutations in the EDA gene, represents the majority of HED cases. Autosomal dominant and recessive forms occasionally occur and result from mutations in at least two other genes: EDAR and EDARADD. EDARADD interacts with the TAB2/TRAF6/TAK1 complex, which is necessary for NF-kappaB activation by EDAR. OBJECTIVES: To determine frequency of EDARADD, TRAF6, TAB2 and TAK1 mutations in HED. MATERIALS AND METHODS: We have screened 28 familial or sporadic HED cases with no mutations in the EDA and EDAR genes for EDARADD, TRAF6, TAB2 and TAK1 mutations. RESULTS: We identified one EDARADD 6-bp homozygous in-frame deletion (c.402-407del, p.Thr135-Val136del) in a patient born to consanguineous parents. Functional studies showed that the p.Thr135-Val136del impaired the EDAR-EDARADD interaction and then severely inhibited NF-kappaB activity. In the remaining 27 patients, we failed to find causative mutations in EDARADD, or in TRAF6, TAB2 or TAK1. CONCLUSIONS: Our study demonstrates that EDARADD mutations are not a frequent cause of HED, while mutations in TRAF6, TAB2 and TAK1 may not be implicated in this disease.

Autosomal dominant anhidrotic ectodermal dysplasias at the EDARADD locus.

Anhidrotic ectodermal dysplasia (EDA) is a disorder of ectodermal differentiation characterized by sparse hair, abnormal or missing teeth, and inability to sweat. X-linked EDA is the most common form, caused by mutations in the EDA gene, which encodes ectodysplasin, a member of the tumor necrosis factor (TNF) family. Autosomal dominant and recessive forms of EDA have been also described and are accounted for by two genes. Mutations in EDAR, encoding a TNF receptor (EDAR) cause both dominant and recessive forms. In addition, mutations in a recently identified gene, EDARADD, encoding EDAR-associated death domain (EDARADD) have been shown to cause autosomal recessive EDA. Here, we report a large Moroccan family with an autosomal dominant EDA. We mapped the disease gene to chromosome 1q42.2-q43, and identified a novel missense mutation in the EDARADD gene (c.335T>G, p.Leu112Arg). Thus, the EDARADD gene accounts for both recessive and dominant EDA. EDAR is activated by its ligand, ectodysplasin, and uses EDARADD to build an intracellular complex and activate nuclear factor kappa B (NF-kB). We compared the functional consequences of the dominant (p.Leu112Arg) and recessive mutation (p.Glu142Lys), which both occurred in the death domain (DD) of EDARADD. We demonstrated that the p.Leu112Arg mutation completely abrogated NF-kB activation, whereas the p.Glu142Lys retained the ability to significantly activate the NF-kB pathway. The p.Leu112Arg mutation is probably a dominant negative form as its cotransfection impaired the wild-type EDARADD's ability to activate NF-kB. Our results confirm that NF-kB activation is impaired in EDA and support the role of EDARADD DD as a downstream effector of EDAR signaling.

[Physiological assessment of a gaseous cryotherapy device: thermal effects and changes in cardiovascular autonomic control]. / Evaluation d'un procédé de cryothérapie gazeuse hyperbare: effets thermiques et modulation vasomotrice neurovégétative.

PURPOSE: The aim of the study was to assess thermal effects and cardiovascular autonomic control with application of a gaseous cryotherapy device to the hand. MATERIAL AND METHODS: Before, during and after cooling of the left hand, we continuously evaluated cutaneous temperature of the right and left hands, as well as heart rate (HR) and arterial blood pressure (BP) and their neurovegetatif control (HR and BP variability) in 8 healthy subjects. Comparison of cooling caused by projection of CO(2) microcrystals (2 min) under high pressure (75 bar) and low temperature (-78 degrees C) to that with application of a latex ice pack (15 min). Assessment of whether cooling triggered any changes in cardiovascular autonomic control, especially as compared with responses by the hand cold-pressure test (2 min). RESULTS: CO(2) projection in the left hand induced a steep decrease (-26 degrees C) in temperature followed by a rapid increase and a cutaneous vasoconstriction of the right hand, with significant increases in BP and cardiac parasympathetic activity. Cardiovascular responses were similar to those with application of the hand cold-pressure test. Application of an ice pack decreased cutaneous temperature to a lesser extent (-19 degrees C) and more slowly, without changing BP or indices of HR and BP variability. CONCLUSION: CO(2) projection caused "thermal shock" and triggered a systemic cutaneous vasoconstriction response, with activation of indices of both ortho- and parasympathetic activity, as with the hand cold-pressure test. Vascular responses during ice pack cooling appeared solely localised to the cooled area, without any significant change in autonomic cardiovascular control.

[Ocular impression test with transfer for the surveillance of vitamin a level]. / Test de l'impression oculaire de transfert pour la surveillance du statut vitaminique A. Premiers résultats en Mauritanie.

This study presents the first results of "impression cytology ocular test" in Mauritania for determination of vitamin A rate. This study is based on the community health centers and is not significative of general population. It's a question in this first study of testing this method, realized in some regions of Mauritania (Nouakchott, Dakhlet Nouadhibou, Hodh Gharby, Inchiri, Adrar, Tiris-Zemmour).