Biomedical subjects

Stéphanie Baulac

Publications and source records attributed to Stéphanie Baulac.

5 recordsLinked to original sources

PubMed2006

Zebrafish lacking Alzheimer presenilin enhancer 2 (Pen-2) demonstrate excessive p53-dependent apoptosis and neuronal loss.

Gamma-secretase cleavage, mediated by a complex of presenilin, presenilin enhancer (Pen-2), nicastrin, and Aph-1, is the final proteolytic step in generating amyloid beta protein found in brains of Alzheimer's disease patients and Notch intracellular domain critical for proper neuronal development. Here, we employ the zebrafish model to study the role of Pen-2 in neuronal survival. We found that (i) knockdown of Pen-2 using antisense morpholino led to a reduction of islet-1 positive neurons, (ii) Notch signaling was reduced in embryos lacking Pen-2 or other gamma-secretase components, (iii) neuronal loss in Pen-2 knockdown embryos is not as a result of a lack of neuronal precursor cells or cell proliferation, (iv) absence of Pen-2 caused massive apoptosis in the whole animal, which could be suppressed by simultaneous knockdown of the tumor suppressor p53, (v) loss of islet-1 or acetylated tubulin positive neurons in Pen-2 knockdown embryos could be partially rescued by knockdown of p53. Our results demonstrate that knockdown of Pen-2 directly induces a p53-dependent apoptotic pathway that contributes to neuronal loss and suggest that Pen-2 plays an important role in promoting neuronal cell survival and protecting from apoptosis in vivo.

Alzheimer Disease↗

PubMed2006

Parental mosaicism can cause recurrent transmission of SCN1A mutations associated with severe myoclonic epilepsy of infancy.

De novo mutations in the SCN1A gene, encoding the alpha1-subunit of the neuronal voltage-gated sodium channel Nav1.1, are the most frequent genetic cause of Severe Myoclonic Epilepsy of Infancy known so far. A few mutations inherited from an asymptomatic or mildly affected parent have been reported, suggesting that expression of the mutated gene may be variable in the transmitting parent. In this study, we report two unrelated families in which two children of unaffected parents had deleterious SCN1A mutations, and show evidence of somatic and germline mosaicism in the transmitting parents. In one of these families, direct sequencing of blood cell DNA was not sufficient to the SCN1A mutation in the transmitting asymptomatic parent who was mosaic for the mutation. We therefore developed a real-time PCR assay to selectively amplify and quantify the mutant allele present at low levels in the transmitting parent in both families. The allele-specific PCR technique used in this study will be of use in detecting other such cases. These findings will have major consequences for the genetic counseling of asymptomatic parents with only one affected child.

Adult↗

PubMed2004

Dimerization of Parkinson's disease-causing DJ-1 and formation of high molecular weight complexes in human brain.

Mutations in the DJ-1 gene have been implicated in the PARK7-linked autosomal recessive form of Parkinson's disease (PD). The molecular properties of DJ-1WT, DJ-1L166P, and a newly identified disease-causing mutant DJ-1M26I were explored after they were transiently expressed in mammalian cells. Treatment of intact, living cells with the chemical crosslinker disuccinimidyl suberate (DSS) revealed that DJ-1WT and mutant DJ-1M26I were present as stable homodimers; DJ-1L166P in particular tended to form high-order complexes as well. In contrast to DJ-1L166P that is quickly degraded by the proteasome, DJ-1M26I was found to be an efficiently expressed and stable variant of DJ-1, suggesting that these mutations have distinct biochemical effects on DJ-1. We further provide evidence that in human brain, under nondenaturing conditions, DJ-1 is present in high molecular weight (HMW) complexes of approximately 250-700 kDa containing parkin, another PD-associated protein.

Animals↗

PubMed2004

Monogenic idiopathic epilepsies.

Major advances have recently been made in our understanding of the genetic bases of monogenic inherited epilepsies. Direct molecular diagnosis is now possible in numerous inherited symptomatic epilepsies. Progress has also been spectacular with respect to several idiopathic epilepsies that are caused by mutations in genes encoding subunits of ion channels or neurotransmitter receptors. Although these findings concern only a few families and sporadic cases, their potential importance is great, because these genes are implicated in a wide range of more common epileptic disorders and seizure types as well as some rare syndromes. Functional studies of these mutations, while leading to further progress in the neurobiology of the epilepsies, will help to refine genotype-phenotype relations and increase our understanding of responses to antiepileptic drugs. In this article, we review the clinical and genetic data on most of the idiopathic human epilepsies and epileptic contexts in which the association of epilepsy and febrile convulsions is genetically determined.

Animals↗

PubMed2004

Fever, genes, and epilepsy.

About 13% of patients with epilepsy have a history of febrile seizures (FS). Studies of familial forms suggest a genetic component to the epidemiological link. Indeed, in certain monogenic forms of FS, for which several loci have been reported, some patients develop epilepsy with a higher risk than in the general population. Patients with generalised epilepsy with febrile seizures plus (GEFS+) can have typical and isolated FS, FS lasting more beyond age 6 years, and subsequent afebrile (typically generalised) seizures. Mutations associated with GEFS+ were identified in genes for subunits of the voltage-gated sodium channel and the gamma2 subunit of the ligand-gated GABAA receptor. Screening for these genes in patients with severe myoclonic epilepsy in infancy showed de novo mutations of the alpha1 subunit of the voltage-gated sodium channel. Antecedent FS are commonly observed in temporal-lobe epilepsy (TLE). In sporadic mesial TLE-characterised by the sequence of complex FS in childhood, hippocampal sclerosis, and refractory temporal-lobe seizures-association studies suggested the role of several susceptibility genes. Work on some large pedigrees also suggests that FS and temporal-lobe seizures may have a common genetic basis, whether hippocampus sclerosis is present or not. The molecular defects identified in the genetic associations of FS and epileptic seizures are very attractive models to aid our understanding of epileptogenesis and susceptibility to seizure-provoking factors, especially fever.

Epilepsy↗