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H Chneiweiss

Publications and source records attributed to H Chneiweiss.

At least 37 records · Page 2Linked to original sources
PubMed1995

Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies). Clinical and neuropathological analysis of 53 patients from three unrelated SCA2 families.

Autosomal dominant cerebellar ataxia type I was diagnosed in three unrelated families from Martinique (French West Indies), and linkage to the locus for spinocerebellar ataxia 2 (SCA2) was established. Neuropathological findings in two patients were those of olivopontocerebellar atrophy without oligodendroglial cytoplasmic inclusions. Cerebellar ataxia was associated with hyporeflexia in 68% of 31 examined patients, with slowed and/or limited eye movements in 65% and with dementia in 29%. No patients had optic atrophy, pigmentary retinal degeneration, spasticity or parkinsonism. Mean age at onset was 33 +/- 16 years, and onset before the age of 20 years was correlated with a more rapid and severe course of the disease. Movement disorders, oculomotor disturbances, sphincter disturbances and cognitive impairment were significantly more frequent in early than in late onset patients. This explains why the phenotype was strikingly different in one family, in which mean age at onset was much earlier. Comparison with previously described SCA2 families indicated similarities, such as reduced saccade velocity, supranuclear ophthalmoplegia and decreased reflexes, although phenotypic heterogeneity remains the outstanding feature of this disorder.

Adolescent↗
PubMed1995

Intraneuronal delivery of protein kinase C pseudosubstrate leads to growth cone collapse.

Axonal navigation during development requires that cues present in the extracellular environment be capable of modifying the structure of the cone in a dynamic way. Protein kinase C (PKC) has long been suspected to be one of the multiple molecular relays present in the terminal structure of the developing axon and involved in the transduction of extracellular signals. The latter proposal is, however, based on the use of drugs or of protocols leading to pleiotropic and often nonspecific effects. In the present study, we have taken advantage of the discovery of a peptide capable of translocating across biological membranes and to accumulate in the cytoplasm and nucleus of cells in culture, to internalize a highly specific peptidic inhibitor of PKC. We demonstrate that linking the two peptides (vector and PKC inhibitor) allows the internalization of the latter in live cells, specifically inhibits PKC and provokes a rapid modification of growth cone morphology. This set of data thus establishes that a peptidic inhibitor of PKC activity, once internalized, provokes a change in growth cone morphology, reminiscent of the collapse phenotype. In addition, the present study describes a new efficient and harmless way to introduce pharmacologically active substances in neural cells in culture.

Amino Acid Sequence↗
PubMed1995

Marked phenotypic heterogeneity associated with expansion of a CAG repeat sequence at the spinocerebellar ataxia 3/Machado-Joseph disease locus.

The spinocerebellar ataxia 3 locus (SCA3) for type I autosomal dominant cerebellar ataxia (ADCA type I), a clinically and genetically heterogeneous group of neurodegenerative disorders, has been mapped to chromosome 14q32.1. ADCA type I patients from families segregating SCA3 share clinical features in common with those with Machado-Joseph disease (MJD), the gene of which maps to the same region. We show here that the disease gene segregating in each of three French ADCA type I kindreds and in a French family with neuropathological findings suggesting the ataxochoreic form of dentatorubropallidoluysian atrophy carries an expanded CAG repeat sequence located at the same locus as that for MJD. Analysis of the mutation in these families shows a strong negative correlation between size of the expanded CAG repeat and age at onset of clinical disease. Instability of the expanded triplet repeat was not found to be affected by sex of the parent transmitting the mutation. Evidence was found for somatic and gonadal mosaicism for alleles carrying expanded trinucleotide repeats.

Adolescent↗
PubMed1995

The gene for spinal cerebellar ataxia 3 (SCA3) is located in a region of approximately 3 cM on chromosome 14q24.3-q32.2.

SCA3, the gene for spinal cerebellar ataxia 3, was recently mapped to a 15-cM interval between D14S67 and D14S81 on chromosome 14q, by linkage analysis in two families of French ancestry. The SCA3 candidate region has now been refined by linkage analysis with four new microsatellite markers (D14S256, D14S291, D14S280, and AFM343vf1) in the same two families, in which 19 additional individuals were genotyped, and in a third French family. Combined two-point linkage analyses show that the new markers, D14S280 and AFM343vf1, are tightly linked to the SCA3 locus, with maximal lod scores, at recombination fraction, (theta) = .00, of 7.05 and 13.70, respectively. Combined multipoint and recombinant haplotype analyses localize the SCA3 locus to a 3-cM interval flanked by D14S291 and D14S81. The same allele for D14S280 segregates with the disease locus in the three kindreds. This allele is frequent in the French population, however, and linkage disequilibrium is not clearly established. The SCA3 locus remains within the 29-cM region on 14q24.3-q32.2 containing the gene for the Machado-Joseph disease, which is clinically related to the phenotype determined by SCA3, but it cannot yet be concluded that both diseases result from alterations of the same gene.

Adult↗
PubMed1995

[Does the ataxo-choreic form of DRPLA exist in Europe? Search of mutation in 120 families].

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by a degeneration of cerebellar and pallidal efferents, more frequent in Japan. Isolated cases are also encountered. Patients present with variable combination of signs including myoclonus, ataxia, epilepsy, choreoathetosis and dementia, with onset from childhood to the seventh decade. Clinically, DRPLA may be undistinguishable from other genetic disorders, in particular Huntington's disease or the spinocerebellar ataxias. The genetic basis of the inherited form of DRPLA is an expansion to more than 49 repeats of an unstable trinucleotide (CAG) in the DRPLA gene on the short arm of chromosome 12. We determined the frequency of this mutation in patients with the DRPLA phenotype. One hundred and seventeen patients with cerebellar ataxia, from 94 families and 23 isolated cases, as well as 3 patients from families with undiagnosed autosomal dominant neurodegenerative disorders were investigated for the presence of the expanded sequence. None of the patients carried this mutation. This finding suggests that DRPLA is rare in the French population. The search for the DRPLA mutation is justified in patients with the DRPLA phenotype, however, since genetic counselling is often requested and neither clinical, nor neuropathological examinations permit a definite diagnosis of the underlying disease.

Atrophy↗
PubMed1994

A third locus for autosomal dominant cerebellar ataxia type I maps to chromosome 14q24.3-qter: evidence for the existence of a fourth locus.

The autosomal dominant cerebellar ataxias (ADCA) type I are a group of neurological disorders that are clinically and genetically heterogeneous. Two genes implicated in the disease, SCA1 (spinal cerebellar ataxia 1) and SCA2, are already localized. We have mapped a third locus to chromosome 14q24.3-qter, by linkage analysis in a non-SCA1/non-SCA2 family and have confirmed its existence in a second such family. We suggest designating this new locus "SCA3". Combined analysis of the two families restricted the SCA3 locus to a 15-cM interval between markers D14S67 and D14S81. The gene for Machado-Joseph disease (MJD), a clinically different form of ADCA type I, has been recently assigned to chromosome 14q24.3-q32. Although the SCA3 locus is within the MJD region, linkage analyses cannot yet demonstrate whether they result from mutations of the same gene. Linkage to all three loci (SCA1, SCA2, and SCA3) was excluded in another family, which indicates the existence of a fourth ADCA type I locus.

Adult↗
PubMed1993

Characterization of PEA-15, a major substrate for protein kinase C in astrocytes.

Astrocytes in the central nervous system are involved in a variety of functions including storage of glycogen, maintenance of the extracellular ionic equilibrium, and support for the migration and the differentiation of neurons. Astrocytes express membrane receptors allowing them to respond to extracellular signals. Activation of receptors induces a cascade of events, such as stimulation of protein kinases and subsequent phosphorylation of target proteins. To understand the regulatory processes underlying neuroglial interactions, attempts were made to identify major phosphorylated proteins in striatal astrocytes, grown in primary culture and labeled with [32P]phosphate. Two-dimensional gel electrophoresis revealed a major doublet, Pa and Pb, of highly labeled spots, with a low molecular weight (M(r) = 15,000) and acidic pI (pI = 5.2 and 5.3, respectively). Using an enriched, heat-stable, cytosolic fraction, Pa and Pb were eluted from semi-preparative two-dimensional gels and subjected to a limited proteolysis and partial microsequencing. The same sequences were obtained within Pa and Pb and had no homology with other known protein. Antibodies raised against corresponding synthetic peptides confirm that the doublet represents two isoelectric variants of the same protein, which also exists under a nonphosphorylated form, N. We propose to name this protein PEA-15, for Phosphoprotein Enriched in Astrocytes-15 kDa, according to its large enrichment in these cells. Treatment of intact astrocytes with 12-O-tetradecanoylphorbol-13-acetate (TPA), which stimulates protein kinase C (PKC), increased the phosphorylation of the more acidic spot (Pb) while decreasing Pa intensity. Stimulations of astrocytes known to increase PKC activity, i.e. noradrenaline, or its inhibition by decreasing extracellular calcium concentrations, staurosporine, or desensitization following long term treatment with TPA, induced a phosphorylation or a dephosphorylation of PEA-15, respectively. Using purified PKC, PEA-15 appeared to be a good substrate in vitro. Two-dimensional peptide mapping revealed that the phosphorylation site in intact cells was identical with the site phosphorylated by PKC in vitro. Mapping the phosphopeptides by HPLC following endolysine C treatment lead to the identification of a sequence, phosphorylated in intact astrocytes and in vitro by PKC, containing a consensus site for PKC: LTRIPSAKK. Antibodies raised against a synthetic peptide derived from this sequence recognized N and Pa in control conditions and Pb after its dephosphorylation. Thus, PEA-15 is an endogenous substrate for PKC, the kinase mediating the transition from Pa to Pb.

Amino Acid Sequence↗
PubMed1993

Phenotypic variability in autosomal dominant cerebellar ataxia type I is unrelated to genetic heterogeneity.

Families with autosomal dominant cerebellar ataxia (ADCA), a heterogeneous group of diseases, were investigated prior to and during genetic linkage analysis. We report here on the clinical features of 122 affected individuals from 36 unrelated families with ADCA type I, the most common type. Our results indicate an anticipation expressed in a mean 9.4 year earlier age at onset and more rapid clinical progression in successive generations. There was no imprinting, since age at onset, disease duration and severity of the disease were independent of parental transmission. Progressive cerebellar ataxia was variably associated with signs such as ophthalmoplegia, dysphagia, sphincter disturbances, briskness or loss of tendon reflexes, decreased vibration sense and amyotrophy, a variability correlated with disease duration. Linkage analysis of 10 informative families with microsatellite markers, located on the short arm of the chromosome 6, allowed the identification of four families showing positive linkage to the SCA1 (spinal cerebellar ataxia 1) locus and six non-SCA1 families for whom linkage to this locus was excluded. This reflects non-allelic genetic heterogeneity. Thus, the analysis of clinical signs associated with cerebellar ataxia in SCA1 versus non-SCA1 kindreds did not distinguish between the two groups. The clinical picture of ADCA type I did not reflect the genetic heterogeneity of the disease.

Adolescent↗
PubMed1993

Genetic heterogeneity of autosomal dominant cerebellar ataxia type 1: clinical and genetic analysis of 10 French families.

We performed linkage analysis between the gene responsible for spinal cerebellar ataxia 1 (SCA1) and the highly polymorphic chromosome 6 locus, D6S89, in 10 French families with autosomal dominant cerebellar ataxia (ADCA) type 1. These families were clinically indistinguishable except for one family with loss of hearing and vision. Very close linkage was observed in four families, with no evidence of recombination between SCA1 and D6S89. Linkage with D6S89 was excluded in the six others, thus demonstrating genetic heterogeneity for ADCA type 1. The D6S89 marker, which is very closely linked to the disease locus, can be used to identify SCA1 families and will lead to predictive testing.

Adult↗
PubMed1992

Expression of transfected stathmin cDNA reveals novel phosphorylated forms associated with developmental and functional cell regulation.

Stathmin is a ubiquitous, highly conserved phosphoprotein, which most likely acts as an intracellular relay integrating various transduction pathways triggered by extracellular signals. Two post-translational isoforms (alpha and beta) have been previously identified whose increasingly phosphorylated forms migrate as a set of isoelectric variant spots (molecular mass 19 kDa; pI 6.2-5.6) on two-dimensional electrophoretic gels. In parallel with the phosphorylation of these forms of stathmin, two sets of three proteins migrating with slightly higher apparent molecular masses (21 and 23 kDa respectively) also incorporated radioactive phosphate in response to cell regulation through various transduction pathways. These phosphoproteins, previously referred to as proteins '16' and '17', share several biochemical properties with stathmin and are recognized by antibodies directed to stathmin or to stathmin peptides. Furthermore, when rat stathmin cDNA was transfected into mouse myogenic C2 cells, it directed the expression of protein sets 16 and 17 together with the 19 kDa forms of stathmin, as detected with a species-specific anti-stathmin antiserum. Proteins 16 and 17 are thus novel phosphorylated derivatives of stathmin, encoded by the same cDNA as its previously identified 19 kDa forms. These results increase the known complexity and diversity of stathmin patterns, which may yield the molecular support for its proposed role as a relay integrating various signals which regulate the proliferation, differentiation and functions of cells during development and adult life.

Animals↗
PubMed1992

Stathmin phosphorylation is regulated in striatal neurons by vasoactive intestinal peptide and monoamines via multiple intracellular pathways.

Stathmin is a ubiquitous soluble protein whose phosphorylation is associated with the intracellular mechanisms involved in the regulations of cell proliferation, differentiation, and functions by extracellular effectors. It is present in the various tissues and cell types as at least two distinct isoforms in their unphosphorylated (Mr approximately 19,000; pI approximately 6.2-6.0) and increasingly phosphorylated forms. Stathmin is particularly abundant in brain, mostly because of its high concentration in neurons, where the protein is a major phosphorylation substrate. In intact striatal neurons grown in primary culture, the cyclic AMP-increasing drug forskolin and the protein kinase C-activating agent 12-O-tetradecanoylphorbol 13-acetate (TPA) induced a potent phosphorylation of stathmin. Their actions were at least partially additive, appearing actually most likely "sequential" on various phosphorylated states of stathmin. Vasoactive intestinal peptide (VIP) reproduced the forskolin-like stimulation but stimulated also other, TPA, and/or Ca2(+)-like protein phosphorylations. These actions of VIP were already maximal after 5 min and were long lasting, still important after 2 h. In addition, concentrations as low as 1 nM were enough to obtain a significant effect, on both cyclic AMP-dependent and independent phosphorylations. Dopamine and the beta-adrenergic agonist isoproterenol were also able to stimulate stathmin phosphorylation, but only with a forskolin-like pattern. Their actions were not additive to those of VIP, confirming previous results on the colocalization of both dopamine D1 and noradrenaline beta 1 receptors with VIP receptors on striatal neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Stathmin phosphorylation patterns discriminate between distinct transduction pathways of human T lymphocyte activation through CD2 triggering.

CD2 triggering of human T lymphocyte activation has been associated with the activation of different interacting protein kinases, including protein kinase C (PKC). However the precise roles of its phosphorylated substrates are still unknown. We show here that PKC-dependent and -independent pathways are responsible for the CD2-induced phosphorylation of stathmin, a ubiquitous soluble phosphoprotein, most likely acting as a general intracellular relay integrating various second messenger pathways. The phosphorylated variants of stathmin provide a fingerprint reflecting the second messenger pathway(s) stimulated. The respective roles of both PKC and stathmin in the regulation of T lymphocyte proliferation are discussed.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1991

Cyclic AMP accumulation induces a rapid desensitization of the cyclic AMP-dependent protein kinase in mouse striatal neurons.

Striatal neurons from the mouse brain embryo grown in primary culture express high levels of cyclic AMP (cAMP)-dependent protein kinase (PKA) activity. To study the modulation of PKA in intact neurons, a rapid method based on Zn(2+)-protein precipitation was developed. This strategy allowed analysis of the stimulation of PKA under conditions of intracellular cAMP concentration increases. Whereas increases up to 1 microM lead to an activation, large and sustained accumulations of cAMP result in a loss of the enzyme activity. With 8-bromo-cAMP (8-Br-cAMP) at 100 microM, the PKA refractoriness occurs within 2 min. It is rapidly reversible because incubation of treated neurons in fresh medium leads to a complete recovery of PKA activity within 30 min. The decrease in assayable PKA does not involve an activation of phosphatases because the histone dephosphorylation rate is not affected by 8-Br-cAMP treatment. Finally, not only 8-Br-cAMP- but also forskolin- and vasoactive intestinal peptide-induced increases in intracellular cAMP concentration can lead to the PKA desensitization. Altogether, these data unravel a new mechanism of PKA regulation.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Dopamine-induced homologous and heterologous desensitizations of adenylate cyclase-coupled receptors on striatal neurons.

Striatal neurons in primary culture express a wide variety of adenylate cyclase-coupled receptors, and particularly dopamine (DA) D1 receptors, which are known to induce an increase in cyclic AMP production. To study desensitization of those receptor-mediated responses, neurons were incubated in the presence of saturating concentrations of DA for various times. We observed a rapid desensitization of the D1 response after 15 min, which reached a maximum after 18 h. This effect is reversible since incubation of treated neurons in fresh medium led to a complete recovery of the dopamine response within 2 days. In addition, a brief treatment with DA resulted in heterologous desensitization of beta-adrenoceptors and 5-HT and vasoactive intestinal peptide (VIP) receptors coupled to adenylate cyclase on striatal neurons. Similar to what was observed for homologous desensitization, these effects are obtained within the first 15 min of exposure to DA; however, they are short-lasting, even in the persistent presence of DA.

Adenylyl Cyclases↗
PubMed1989

Intracellular substrates for extracellular signaling. Characterization of a ubiquitous, neuron-enriched phosphoprotein (stathmin).

We previously identified (Sobel, A., and Tashjian, A. H., Jr. (1983) J. Biol. Chem. 258, 10312-10324) a group of cytoplasmic proteins whose phosphorylation could be related to the regulation by extracellular effectors of cells as different as pituitary and muscle cells. Among these phosphoproteins, proteins "7" and "8" (Mr approximately 19,000, pI approximately 5.8-6.0), that we now designate P1 and P2, are very abundant in rat brain. Partial purification of these proteins was therefore achieved after 100 degrees C precipitation of a rat brain-soluble fraction and further fractionation of the supernatant by ion exchange chromatography. Several related non-phosphorylated (N1, N2) and phosphorylated (P3) proteins were also identified in the heat-resistant supernatant. Antisera raised against P2 extracted from nitrocellulose blots of semipreparative two-dimensional gels recognized all the proteins N1, N2, P1, P2, and P3, confirming that they belong to the same protein family, and suggesting that they are likely various forms of a single protein core. The same protein could be detected biochemically and immunologically at various concentrations in all the tissues or cell types from diverse mammalian and nonmammalian species tested. Together with our previous data relating its phosphorylation to the regulation of the proliferation, differentiation, and/or the functions of the cells considered, this observation leads us to suggest that it might be an ubiquitous regulatory phosphoprotein playing the role of an intracellular "relay" for extracellular signals, after their binding to specific membrane receptors and the generation of second messengers. We propose to name this protein stathmin, from the greek "stathmos" (relay).

Animals↗
PubMed1989

Cyclic AMP reduces adhesion of isolated neuronal growth cones from developing rat forebrain to an astrocytic cell line from embryonic mouse striatum.

We have recently shown that isolated neuronal growth cones from developing rat forebrain possess an appreciable activity of adenylate cyclase, producing cyclic adenosine monophosphate, which can be stimulated by various neurotransmitter receptor agonists and by forskolin [Lockerbie R. O., Hervé D., Blanc G., Tassin J. P. and Glowinski J. (1988) Devl Brain Res. 38, 19-25]. In the present study, we have investigated the effect of cyclic adenosine monophosphate in an in vitro adhesion assay established between [3H]GABA-labelled isolated growth cones and a Simian virus-40 transformed astrocytic cell line from embryonic mouse striatum. Adhesion of the isolated growth cones onto the astrocytic clone increased steadily up to about 45 min before it began to level off at ca 16-18% of total [3H]GABA-labelled isolated growth cones added. Adhesion of the isolated growth cones onto the astrocytic clone was much superior to that seen on polyornithine and, in particular, on non-treated tissue culture wells. Adhesion "at plateau" was independent of both temperature and extracellular Ca2+ and was markedly reduced (ca 50%) by trypsin pre-treatment of the isolated growth cones. Pre-treatment of the isolated growth cones with either forskolin or lipophilic analogues of cyclic adenosine monophosphate attenuated adhesion in a time- and concentration-dependent manner. Approximately 30% reduction in adhesion to the astrocytic clone "at plateau" was observed after a 15 min pre-treatment of the isolated growth cones with forskolin at 10(-4) M or cyclic adenosine monophosphate analogues at 10(-3) M. A cyclic guanosine monophosphate analogue was without effect on adhesion of isolated growth cones. Scanning electron microscope analysis showed that isolated growth cones pre-treated with either cyclic adenosine monophosphate analogues or forskolin had a simpler morphology when attached to the astrocytic clone than isolated growth cones under control conditions. Pre-treatment of the isolated growth cones with low concentrations of cyclic adenosine monophosphate analogues increased protein kinase activity, measured using an exogenous histone phosphate acceptor, to a level which could not be further stimulated by cyclic adenosine monophosphate. Pre-treatment with a cyclic guanosine monophosphate analogue produced the same effect but only at much higher concentrations than those required for cyclic adenosine monophosphate analogues.

Animals↗