Prion diseases: disease diversity and therapeutics]

More than one hundred victims of iatrogenic CJD with cadaveric dura mater grafting have been recognized in Japan, and the people have been also exposed to a risk of outbreaks of variant CJD. These diseases are distinct from other forms of prion diseases as well as other neuropsychiatric disorders, but on an early clinical stage, their differential diagnoses from other atypical forms of prion diseases are not necessarily easy. Thus, atypical forms of prion diseases were overviewed and discussed here. In addition, data on recent clinical trials of enteral antimalarial drug (quinacrine or quinine) treatment or intracerebroventricular pentosan polysulfate treatment were presented and discussed, because research progress in the therapeutics for prion diseases has been remarkably made on the basis of the prevalence of those acquired forms of prion diseases.     

Prion diseases

The prion diseases (PrDs) have received considerable attention in recent years, primarily as a result of heightened concern about the risk that bovine spongiform encephalopathy (mad cow disease) and other animal borne PrDs pose to humans. Although rare, the PrDs represent an important group of dementias that behave as both neurodegenerative and infectious diseases. The following review details the clinical and pathologic phenotypes of the major expressions of PrD in humans and the current approach to their diagnosis. The historical aspects leading to the recognition of these diseases and the theories regarding the pathogenesis and the transmissible nature of prions are also addressed.     

Prion diseases

Prion diseases are one of the paradigms of modern neurological nosology founded on molecular grounds. Their incidence is low, however the public health challenges derived from their transmissibility, especially due to the appearance of a variant of Creutzfeldt-Jakob disease (vCJD) confers them a preferential place among health care authority concerns. The evolution of data from the European surveillance systems suggests a generalized underdiagnosis of prion diseases and casts doubts about their ability to detect a possible second wave of atypical vCJD, especially if their clinical-pathological characteristics change. Recent data also challenge the feasibility of a subclassification of prion diseases according to their genetic-molecular features     

Prion diseases

Prion diseases are degenerative disorders of the nervous system caused by transmissible particles that contain a pathogenic isoform of the prion protein, a normal constituent of cell membranes. The most common human prion disease is Creutzfeldt-Jakob disease (CJD). Most cases are sporadic with unknown mode of transmission, 10-15% of cases are inherited, and a small number have been transmitted by medical procedures. The spread of human prion diseases through consumption of infected material has been implicated historically in kuru and recently in variant CJD. Animal prion diseases (scrapie of sheep, transmissible mink encephalopathy, chronic wasting disease of cervids, and bovine spongiform encephalopathy) all seem to be laterally transmitted by contact with infected animals or by consumption of infected feed. The different modes of transmission of different prion diseases, the unpredictable species barriers, the variable distribution of infectivity in tissues, and strain variations found in some diseases all make risk assessment and predictions of future events difficult.     

Prion diseases

Prion diseases are incurable neurodegenerative conditions affecting both animals and humans. They may be sporadic, infectious, or inherited in origin. Human prion diseases include Creutzfeldt-Jakob desease (CJD), Gerstmann-Straussler-Scheinker disease, kuru, and fatal familial insomnia. The appearance of variant CJD, and the demonstration that is caused by strains indistinguishable from bovine spongiform encephalopathy (BSE) in cattle, has led to the threat of a major epidemic of human prion disease in the UK and other countries where widespread dietary exposure to bovine prions has occurred. This article reviews the history and epidemiology of these diseases, and then focuses on important areas of current research in human prion disorders.     

Prion病与睡眠障碍

Prion病是由传染性朊蛋白侵袭中枢神经系统引起的致死性神经变性脑病,睡眠障碍在Prion病中十分常见,也是其诊断特征之一.其中致死性家族性失眠症表现为严重的生理睡眠缺失及特殊梦幻状态、自主神经功能失调和过度运动;多导睡眠图早期睡眠纺锤波和K复合波消失,无法产生快速眼动和非快速眼动睡眠生理循环.除PET扫描呈现丘脑低代谢,神经病理学观察可见丘脑神经元大量缺失,尤其是丘脑前核和背内侧核.尽管睡眠障碍亦常见于Creutzfeldt-Jakob病患者,但并非该疾病特征,仅是丘脑受累标志;多导睡眠图所见频繁觉醒,除与丘脑神经元退行性改变有关外,可能还与朊蛋白生物学功能障碍即朊蛋白病发病的共同机制有关.     

MSA update]

Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder characterized by various combinations of parkinsonism, cerebellar ataxia and autonomic failure. Although the clinical entities of olivopontocerebellar atarophy (OPCA), striatonigral degneratin (SND) and Shy-Drager syndrome have been conventionally used, recent identification of oligodendroglial cytoplasmic inclusions (GCIs) as the pathognomonic findings has established the clinicopathological entity of MSA. Epidemiological studies in Japan have shown that MSA is the most common form of sporadic ataxia. Among the various clinical forms of MSA, OPCA has been shown to be the most common form. Although MSA has been regarded as a sporadic disease, familial occurrence has recently been identified. Integrated analyses of non-parametric linkage analyses on the familial MSA cases and association studies on sporadic MSA cases are expected to accelerate the studies on identification of genes involved in the pathogenesis of MSA.     

Channelopathy update]

Electrophysiological techniques, molecular technology and molecular genetics have been quickly developed in the late 20th century. Now many genetical abnormalities of channel proteins including voltage gated ion channels, ligand gated ion channels and Ca induced Ca channel have been discovered. In this article, I briefly review these genetical abnormality of ion channels ("channelopathies") and the pathophysiological background of these channelopathies.     

Prion proteins: a biological role beyond prion diseases

The biological role of the scrapie isoform of prion protein (PrP(Sc)) as an infectious agent in numerous human and non-human disorders of the central nervous system is well established. In contrast, and despite decades of intensive research, the physiological function of the endogenous cellular form of the prion protein (PrP(C)) remains elusive. In mammals, the ubiquitous expression of PrP(C) suggests biological functions other than its pathological role in propagating the accumulation of its misfolded isotype. Other functions that have been attributed to PrP(C) include signal transduction, synaptic transmission and protection against cell death through the apoptotic pathway. More recently, immunoregulatory properties of PrP(C) have been reported. We review accumulating in vitro and in vivo evidence regarding physiological functions of PrP(C).     

Inherited dystonia update]

Among idiopathic dystonia, inherited dystonia whose causative gene or linkage has been clarified are named as DYT1 to DYT15. The causative genes of DYT1, 5 and 11 were identified as genes of Torsin A, GTP cyclohydrolase I, and epsilon-sarcoglycan, respectively. All three are inherited dominantly. DYT1, and DYT5 which is known as Segawa disease, are dystonia with onset in childhood. After identification of the causative gene, each disorder was found to show the various phenotypes. In both DYT1 and Segawa disease, early onset develops generalized dystonia, and later onset focal or segmental dystonia. Deep brain stimulation of globus pallidus internal segment shows remarkable effect on DYT1. Segawa disease responds markedly to L-dopa without any side effect lifelong. The pathophysiology of Segawa disease is that partial deficiency of BH4 resulted from GCH I deficiency, rate limiting enzyme of synthesis of BH4, affects the TH activity at terminal of nigrostriatal dopamine neuron. The role of Torsin A in the pathogenesis of DYT1 is unknown. For a certain neuron or neuronal system to manifest a clinical symptom, it should reach to a certain maturational level. The symptoms of inherited dystonia are influenced by the developmental level of responsible neuron or neuronal circuit.     

Mitochondrial diseases: a nosological update

Mitochondrial diseases are disorders caused by impairment of the mitochondrial respiratory chain, characterized by clinical-genetic heterogeneity and frequent multisystemic involvement. It is difficult to establish a precise genotype/phenotype correlation and obtain a definitive nosology. Today's genetic classification distinguishes disorders caused by defects in the mitochondrial genome (sporadic or maternally-inherited) from disorders caused by defects in the nuclear genome (autosomally-inherited). We report an updated classification, briefly review the main clinical syndromes and describe the most recent genetic knowledge.     

Prion protein structure and its relationships with pathogenesis]

In order to explore the structural domains of prion protein (PrP) that are required for the isoform conversion, prion formation and neurodegenerative effects, we designed a series of PrP deletion mutants and studied, using prion-infected cultured cells and transgemic (Tg) mice, 1) if these mutants can be converted to the abnormal isoform, 2) constitute prions, and 3) cause neurodegeneration when converted and accumulated in mouse brains. We discovered that a mutant PrP with deletions at the N-terminus and the middle portion retained all the three abilities. The molecule named PrP106 was composed of 106 amino acids, nearly a half of 208 composing wild type PrP. The abnormal isoform of PrP106 (PrPSc106) that had been purified from prion-infected Tg mice proved to share, with the abnormal isoform of wild type PrP (PrPSc), unique properties such as high beta-sheet content and propensity to form fibrous aggregates. These findings rationalized the structural analysis of PrPSc106 in comparison with PrPSc. The structure of 2D crystals of the two abnormal PrP isoforms was studied using electron-microscopy, and the data helped to make the 3D structural model of abnormal PrP isoform. Studies with Tg mice expressing other mutant PrPs are currently under way.     

Prion protein genes and prion diseases: studies in transgenic mice

In the past decade, manipulation of PrP genes by transgenesis in mice has provided important insights into mechanisms of prion propagation and the molecular basis of prion strains and species barriers. Despite these advances, our understanding of these unique pathogens is far from complete. This review focuses on PrP gene knockout and gene replacement studies, PrP structure and function, and transgenic models of human and animal prion diseases. Transgenic approaches will doubtless remain the cornerstone of investigations into the prion diseases in the coming years, which will include mechanistic studies of prion pathogenesis and prion transmission barriers. Transgenic models will also be important tools for the evaluation of potential therapeutic agents for prion diseases.     

Prion diseases: a riddle wrapped in a mystery inside an enigma

It is now widely accepted that many structurally diverse proteins can misfold and cause so-called "conformational diseases", including the most common neurodegenerations, Alzheimer's disease and Parkinson's disease. The conversion of largely a-helical or random coil proteins into cross-beta-pleated sheet conformations that form first oligomers and then fibrils underlies these disorders. However, this alpha- to beta-structure transition seems to be a generic propensity of all globular proteins, not only those involved in neurodegenerations, not to mention "prion diseases". Metaphorically, all these neurodegenerations are "infectious" in the sense that misfolded beta-sheeted conformers are formed in a nucleation process in which preformed metastable oligomer acts as a seed (a nucleus) to convert a normal into an abnormal protein. However, in none but transmissible spongiform encephalopathies (TSEs) has infectivity in a microbiological sense ever been observed, and even in TSEs the formation of misfolded protein is not necessarily accompanied by the generation of infectivity de novo. Furthermore, certain "prion diseases" are not TSEs but just "proteinopathies" caused by accumulation of abnormally misfolded PrPd. The presence of a massive amount of PrP-amyloid and no infectivity casts doubts on whether TSEs are really infectious amyloidoses. The misfolding of PrP may yet prove to be an epiphenomenon secondary to infection with a still unknown infectious agent. If, on the other hand, the purely proteinaceous character of the replicating unit of TSE infectivity is ultimately found to be correct, the critical issues become 1) the mechanism by which a misfolded PrP template induces normal protein molecules to adopt the same pathologically misfolded conformation, and 2) the intracellular conditions that are responsible for strain differences in these molecules.     

Prion diseases - current theories and potential therapies: a brief review

Prion diseases are a group of infectious diseases that cause lethal neurodegenerative disorders in both humans and animals. Affected patients usually die within one year from the appearance of the first clinical abnormalities. Unfortunately, no viable treatment options are available for prion diseases. The aim of this review is to describe the underlying prion disease pathology and discuss the therapeutic targets that have emerged from this.     

Prion infections, blood and transfusions

Prion infections lead to invariably fatal diseases of the CNS, including Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE), and scrapie in sheep. There have been hundreds of instances in which prions have been transmitted iatrogenically among humans, usually through neurosurgical procedures or administration of pituitary tissue extracts. Prions have not generally been regarded as blood-borne infectious agents, and case-control studies have failed to identify CJD in transfusion recipients. Previous understanding was, however, questioned by reports of prion infections in three recipients of blood donated by individuals who subsequently developed variant CJD. On reflection, hematogenic prion transmission does not come as a surprise, as involvement of extracerebral compartments such as lymphoid organs and skeletal muscle is common in most prion infections, and prions have been recovered from the blood of rodents and sheep. Novel diagnostic strategies, which might include the use of surrogate markers of prion infection, along with prion removal strategies, might help to control the risk of iatrogenic prion spread through blood transfusions.