TDP‐43 in amyotrophic lateral sclerosis – is it a prion disease?

Amyotrophic lateral sclerosis is a devastating disease characterized by rapidly progressive paresis. The neuropathological hallmark of most amyotrophic lateral sclerosis cases are neuronal and glial aggregates of phosphorylated 43‐kDa TAR DNA‐binding protein (pTDP‐43). The accumulation of similar proteins into insoluble aggregates is now recognized as a common pathological hallmark of neurodegenerative diseases in general. Importantly, many of these proteins such as tau and amyloid‐β in Alzheimer's disease and α‐synuclein in Parkinson's show a stereotypical sequential distribution pattern with progressing disease. In this review, we discuss recent evidence that TDP‐43 in ALS may propagate similarly to other neurodegenerative disease proteins. We furthermore delineate similarities and important differences of TDP‐43 proteinopathies to prion diseases.     

Peptide aptamer-mediated modulation of prion protein α-cleavage as treatment strategy for prion and other neurodegenerative diseases

正Despite intensive research,most neurodegenerative diseases cannot be cured and for some of them no treatment is available to increase survival or quality of life.Among the latter are prion diseases,fatal and transmissible neurodegenerative diseases of humans and other animals.Exam-     

散发性Creutzfeldt-Jakob病患者10例prion基因研究

目的 检测10例Creutzfeldt-Jakob病（CJD）患者prion基因（PRNP）外显子突变情况.方法 抽取患者外周静脉血,提取DNA,PCR法扩增PRNP外显子后直接测序,并用限制性内切酶Nsp Ⅰ检测PRNP 129位点密码子基因型.结果 2例肯定CJD患者中,1例PRNP检测未见异常,另1例PRNP第729碱基G被C取代（729G→C）,使编码prion第211个氨基酸的密码子GAG变成了GAC,翻译后第211个氨基酸由谷氨酸变为天冬氨酸（E211D）.8例很可能CJD患者中,2例PRNP第751碱基G被A取代（751G→A）,使编码prion第219个氨基酸的密码子GAG变成了AAG,翻译后第219个氨基酸由谷氨酸变为赖氨酸（E219K）.10例CJD患者PRNP 129位点密码子基因型都是甲硫氨酸纯合型.结论 1例肯定CJD患者的prion基因外显子存在一种新的点突变E211D,这很可能是导致遗传prion病发生的原因.2例很可能CJD患者的prion基因突变E219K,与M129V同属于基因多态性,而不是致病原因.prion基因检测有助于prion病的诊断.     

Clinicopathologic characteristics of sporadic Japanese Creutzfeldt–Jakob disease classified according to prion protein gene polymorphism and prion protein type

We analyzed neuropathologic features of 23 Japanese patients with sporadic Creutzfeldt–Jakob disease (sCJD) by means of prion protein (PrP) immunolabeling associated with codon 129 polymorphism of the PrP gene and western blot analysis of protease-resistant PrP (PrP type). Clinical features, particularly age at onset, disease duration, periodic synchronous discharge and presence of myoclonus, were also analyzed. This study included 11 cases of subacute spongiform encephalopathy (SSE), 10 cases of panencephalopathic (PE)-type sCJD and two cases of thalamic-type sCJD, classified according to cerebral pathology findings. According to PrP gene polymorphism and PrP type, 18 cases were classified as MM1-type, two as MV1-type, two as MM2-type and one as MM1 + 2-type sCJD. SSE and PE-type sCJD showed similar clinical features, with the exception of disease duration, codon 129 polymorphism and PrP type. Thalamic-type sCJD showed different clinical features and PrP type. We suggest that SSE and PE-type sCJD comprise the sCJD subtype and that PE-type sCJD is a prolonged pathologic phenotype of SSE. When we compare our results with those from a series of Caucasian sCJD patients, the percentages of codon 129 polymorphisms differed, as did classification based on PrP gene polymorphism and PrP type; our series included many PE-type sCJD cases and disease duration was relatively long and MM2-type cases showed clinicopathologic variability.     

ADAM proteases: protective role in Alzheimer's and prion diseases?

Alzheimer's disease, as well as most of other neurodegenerative disorders, is characterized by the deposition of insoluble proteinaceous aggregates. Hence, any intervention aimed at reducing this process could be envisioned as a therapeutic way to slow down the disease. In the case of Alzheimer's disease, the culprit protein is the 40-43 amino acid-long amyloid beta peptide (Abeta). This fragment is generated from the beta-amyloid precursor protein (betaAPP) by two distinct enzymes, namely the beta- and the gamma-secretases. In the past years, a tremendous effort has been made to develop potent and specific inhibitors of these proteolytic activities. Beside these Abeta-forming proteases, a third cleavage performed by the so-called alpha-secretase takes place in the middle of the Abeta sequence and not only precludes its formation but also generates the secreted product sAPPalpha that possesses neurotrophic and neuroprotective properties. This beneficial cleavage has been shown to be strongly upregulated by protein kinase C (PKC) agonists and to be, at least partially, triggered by ADAM proteases (A Disintegrin And Metalloprotease). Recently, a proteolytic attack with similar characteristics has been shown to occur in the middle of the "toxic" 106-126 domain of the prion protein (PrPc), which PrPsc isoform is the causative agent of transmissible spongiform encephalopathies. As both Abeta and PrP(106-126) trigger neurotoxicity and cell death, this ADAM-dependent proteolytic attack could represent a valuable therapeutic target in order to deplete cells from these endogenous "toxins"and prevent the associated aggregates usually detected in affected brains.     

Mutant prion protein D202N associated with familial prion disease is retained in the endoplasmic reticulum and forms ‘curly’ intracellular aggregates

Transmissible Spongiform Encephalopathies are fatal neurodegenerative disorders of humans and animals that are familial, sporadic, and infectious in nature. Familial disorders of humans include Gerstmann–Straussler–Scheinker disease (GSS), familial Creutzfeldt–Jakob disease (CJD), and fatal familial insomnia, and result from point mutations in the prion protein gene. Although neurotoxicity in familial cases is believed to result from a spontaneous change in conformation of mutant prion protein (PrP) to the pathogenic PrP-scrapie (PrP^Sc) form, emerging evidence indicates otherwise. We have investigated the processing and metabolism of mutant PrP D202N (PrP^202N) in cell models to elucidate possible mechanisms of cytotoxicity. In this report, we demonstrate that PrP^202N expressed in human neuroblastoma cells fails to achieve a mature conformation following synthesis and accumulates in the endoplasmic reticulum as ‘curly’ aggregates. In addition, PrP^202N cells show increased sensitivity to free radicals, indicating that neuronal susceptibility to oxidative damage may account for the neurotoxicity observed in cases of GSS resulting from PrP D202N mutation. Yaping Gu and Susamma Verghese contributed equally.     

Cellular prion protein participates in amyloid-β transcytosis across the blood-brain barrier

The blood-brain barrier (BBB) facilitates amyloid-β (Aβ) exchange between the blood and the brain. Here, we found that the cellular prion protein (PrP(c)), a putative receptor implicated in mediating Aβ neurotoxicity in Alzheimer's disease (AD), participates in Aβ transcytosis across the BBB. Using an in vitro BBB model, [(125)I]-Aβ(1-40) transcytosis was reduced by genetic knockout of PrP(c) or after addition of a competing PrP(c)-specific antibody. Furthermore, we provide evidence that PrP(c) is expressed in endothelial cells and, that monomeric Aβ(1-40) binds to PrP(c). These observations provide new mechanistic insights into the role of PrP(c) in AD.     

Faut-il répéter l’angiographie cérébrale après hémorragie sous-arachnoïdienne périmésencéphalique ?

BACKGROUND AND PURPOSE: In patients with perimesencephalic subarachnoid hemorrhage (pSAH) DSA is recommended to exclude aneurysms to due false negative findings in CT-angiography. However, whether a second DSA is indicated during the clinical course to exclude--in addition to aneurysms--fistulas, too, is still under debate. We aimed to evaluate the benefit of repeated DSA in patients with pSAH. METHODS: The source of data was a prospective database set up at the neurological, neurosurgical and neuroradiological departments in our institution. A total of 69 patients with pSAH were enrolled and analyzed by reviewing the medical records and neuroradiological findings. RESULTS: 68 patients presented with Hunt & Hess Grade I-II and one patient with Hunt & Hess Grade III. Median in-hospital stay was 8 days (3-22). In 2 patients mild vasospasm were diagnosed. DSA was performed in all patients at least once. DSA was repeated in 38 patients (55%) after a median of 7 (3-21) days. None of the repeated DSA did show any additional distinctive features with respect to the first DSA. CONCLUSIONS: In our opinion the procedure of repeating DSA in patients with pSAH is likely to become obsolete. One DSA should be performed prior to discharge--and subsequent to possible vasospasm--to exclude hemorrhage caused by aneurysms of the posterior circulation mimicking a perimesencephalic SAH pattern.     

Analysis of the polymorphic prion protein gene codon 129 in idiopathic Parkinson’s disease

Summary. Idiopathic Parkinson’s disease (IPD) is a neurodegenerative disorder of unknown aetiology. Histopathological similarities between IPD and Creutzfeldt-Jakob prion disease (CJD) have been suggested. Homozygosity at polymorphic prion protein gene codon 129 (PRNP129) is a risk factor for developing CJD. Therefore we investigated a putative genetic link between CJD and IPD by studying PRNP129 genotype segregation in 81 patients with IPD. We did not ascertain a different PRNP129 genotype distribution in IPD patients compared to healthy Germans. We found a significant difference in PRNP129 genotype in dependence of the clinical predominance type of IPD. Patients with tremor-dominant IPD presented less frequent a methionine homozygosis at PRNP129 than hypokinetic-rigid IPD patients (30% versus 62.5%; p < 0.033). In conclusion, genotype distribution at codon 129 is obviously not essential in determining IPD. But our results may provide first evidence of an association between certain PRNP129 polymorphisms and the clinical presentation of IPD. Both authors contributed equally to this work Present addresses: Institute of Reconstructive Neurobiology, Hertie Foundation, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany; Schering AG, Clinical Development CNS, Sellerstrasse 31, 13342 Berlin, Germany     

L'arrêt du sport intensif : révélation d'addictions ?

This study aims to show the impact of ending intensive sport activities on the psychic life of two former high level sportsmen and this under a psychoanalytical point of view. The question is to know whether ending intensive sport activities can be at the origin of an addiction of replacement (knowing meanwhile that the sportsman cannot accept the loss of his high level athlete statute) and whether the depression and the drop in self-esteem at the end of a sportsman's career are inevitable. The ending of a sportsman's career also puts an end to his quasi-pathological identity research, research which could be compared to a borderline behaviour. Moreover, a high level sportsman is more vulnerable at the end of his career and can be much more inclined to become dependent on drugs or on other addictions. During his career two distinct worlds surround him: the sporting family of adoption and the family unit. We can therefore question whether the sportsman dissociates these two families on a psychical level in order not to fall into a depression or into another dependence. Stopping sport activities is thus synonymous with a total loss of oneself; and this can therefore involve an anguish of separation and a probable fall into a social vacuum and into addiction.     

Saccharomyces cerevisiae in neuroscience:how unicellular organism helps to better understand prion protein?

The baker's yeast Saccharomyces(S.)cerevisiae is a single-celled eukaryotic model organism widely used in research on life sciences.Being a unicellular organism,S.cerevisiae has some evident limitations in application to neuroscience.However,yeast prions are extensively studied and they are known to share some hallmarks with mammalian prion protein or other amyloidogenic proteins found in the pathogenesis of Alzheimer's,Parkinson's,or Huntington's diseases.Therefore,the yeast S.cerevisiae has been widely used for basic research on aggregation properties of proteins in cellulo and on their propagation.Recently,a yeast-based study revealed that some regions of mammalian prion protein and amyloidβ1–42 are capable of induction and propagation of yeast prions.It is one of the examples showing that evolutionarily distant organisms share common mechanisms underlying the structural conversion of prion proteins making yeast cells a useful system for studying mammalian prion protein.S.cerevisiae has also been used to design novel screening systems for anti-prion compounds from chemical libraries.Yeastbased assays are cheap in maintenance and safe for the researcher,making them a very good choice to perform preliminary screening before further characterization in systems engaging mammalian cells infected with prions.In this review,not only classical red/white colony assay but also yeast-based screening assays developed during last year are discussed.Computational analysis and research carried out using yeast prions force us to expect that prions are widely present in nature.Indeed,the last few years brought us several examples indicating that the mammalian prion protein is no more peculiar protein–it seems that a better understanding of prion proteins nature-wide may aid us with the treatment of prion diseases and other amyloid-related medical conditions.     

Surmortalité dans un hôpital psychiatrique pendant la guerre (Leyme) : cas particulier ou représentatif ?

A number of studies have highlighted the above-average death rate of psychiatric patients during World War II due to major food deficiency. The authors studied the death rate in the psychiatric hospital of the Lot department during this period. The fact that the medical establishment was in an agricultural area probably helped protect the patients, this is underlined even though according to death certificates, a total of 26 patients died of causes related to food or medicine deficiency. Through a perusal of documents of the period, it seems that many psychiatrists vigorously protested against the living conditions reserved for their patients.     

Psychose hystérique : solution psychotique à l’irruption de la sexualité génitale ?

The notion of hysterical psychosis implies the paradox of a psychotic genitality. Leaning on the psychoanalytic, phenomenological and gestaltist approach of Gisela Pankow, we try to define this nosographic entity, by underlining in a patient a special kind of relationship with imagos and own body we called dialectic of penetration. In that kind of pathological functioning, De Clérambault's syndrome could be understood as the realization, in the psychotic experience area, of a sort of intrusive genital sexuality, and delusion as a new performance of œdipal drama on the delusional scene. We finally question the place of a lacunar Oedipus complex in non-schizophrenic psychoses.     

Les dyskinésies paroxystiques kinésigéniques : une « canalopathie » ? Étude de 19 cas

Introduction

Paroxysmal kinesigenic dyskinesia (PKD) is characterized by brief episodes of dystonia and choreoathetosis triggered by sudden voluntary movements. Disease onset is seen in the first or second decade. The attacks typically last less than one minute. Three autosomal dominant PKD loci are identified: EKD1, EKD2 and EKD3. EKD1 has an overlap with the locus of the “Infantile Convulsion and Choreoathetosis (ICCA) syndrome”. The favorable natural history, the episodic nature of the symptoms and their sensitivity to anticonvulsant therapy suggest channelopathy as a mechanism of PKD.

Patients and methods

We reviewed the clinical features, the family history, the treatment response, the evolution and the technical investigations in 19 affected individuals.

Results

All cases were idiopathic. Ten patients had a positive familial history. Three patients suffered from ICCA syndrome. Some atypical features were seen, such as the association of kinesigenic and nonkinesigenic attacks and the presence of migraine, ataxia, seizures and myoclonus. Acetazolamide responsiveness was seen in two patients.

Conclusion

The coexistence of PKD and nonkinesigenic dyskinesia in several patients confirms the earlier described presence of intermediary forms, nonrepresented in the current classification of paroxysmal dyskinesias. Our study results suggest channel dysfunction and basal ganglia involvement in the pathophysiology of PKD.