Does PRNP gene control the clinical and pathological phenotype of human spongiform transmissible encephalopathies?

BACKGROUND: Human spongiform transmissible encephalopathies (TSE) are a group of neurodegenerative diseases caused by a transmissible not yet recognized agent; their distinctive neuropathological features are astrocytosis, spongiform lesions of the neuropil, neuronal loss and occasionally amyloid plaques in the cortical and subcortical gray matter. TSE are biochemically characterized by the deposition in the nervous system of an amyloid-type protein, PrPres derived from the post-translational modification of a normal protein, PrPsen. The expression of this protein is controlled by the PRNP gene mapped on chromosome 20 in man. A number of point mutations of the PRNP gene have been described in the familial forms of these TSE. Some of these mutations have been associated with differences in the phenotypic expression of the disease. MATERIAL AND METHODS: This study was designed to verify whether it was possible to identify a selective phenotype depending upon a given PRNP modified genotye; for this purpose, a group of familial TSE cases (CJD 210ILE, CJD 201LYS, FFI 178ASN) were selected and their neuropathological profiles have been compared with those of a large series of sporadic CJD cases. RESULTS: No significant differences were found between the topography and severity of lesions in the cerebral cortex, cerebellum, hippocampus, basal ganglia and thalamus between the two groups. Two differences were found: the clinical duration of the disease which appeared significantly (p = 0.02) shorter in the 210ILE-mutated cases compared to that of non-mutated sporadic cases. The highly selective vulnerability of thalamus in FFI showing a severe pathology especially in its dorso-medial part in comparison with that of the sporadic CJD cases. CONCLUSION: The results of this study confirm that the different polymorphism at codon 129 of the PRNP gene, which could be involved in the structural "domains" of human PrP, might modulate the pathological phenotype of TSE.     

Gerstmann-Str?ussler-Scheinker syndrome,fatal familial insomnia, and kuru: a review of these less common human transmissible spongiform encephalopathies.

Creutzfeldt-Jakob disease (CJD), Gerstmann-Str?ussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI) and kuru constitute major human prion disease phenotypes. Each has been successfully transmitted in animal models and all are invariably fatal neurodegenerative disorders, with the brains of affected individuals harbouring variable amounts of an abnormal, protease-resistant form of the prion protein (PrPres), which is inextricably linked to pathogenesis and transmissibility. Classical sporadic CJD is the most common human transmissible spongiform encephalopathy (TSE), but recently the variant form (vCJD), first described in the UK in 1996, has drawn considerable attention. In contrast to sporadic CJD, FFI and GSS are almost invariably genetically determined TSEs, caused by a range of mutations within the open reading frame of the prion protein gene (PRNP) on chromosome 20. By definition, the nosologic term FFI is reserved for patients manifesting prominent insomnia, generally in combination with dysautonomia, myoclonus, and eventual dementia, with the predominant pathologic changes lying within the thalami and a specific underlying mutation in PRNP. GSS, however, encompasses a more diverse clinical spectrum ranging from progressive cerebellar ataxia or spastic paraparesis (both usually in combination with dementia), to isolated cognitive impairment resembling Alzheimer's disease. Additional extra-pyramidal features, which may respond to dopaminergic therapy can also be seen. Neuropathological findings are also relatively diverse, partly overlapping with those found in Alzheimer's disease, especially the presence of neurofibrillary tangles (NFTs). Although GSS and FFI in their classical forms are differentiable clinical profiles, such divisions may have no intrinsic biological validity given the considerable intra-familial clinico-pathological diversity so commonly seen. Kuru constitutes a horizontally transmitted prion disease, which after a lengthy incubation period, presents clinically as a progressive cerebellar ataxia associated with tremors. It has now almost disappeared since the cessation of ritualistic endocannibalism in the late 1950s but was previously exclusively endemic amongst the Fore linguistic group and neighbouring tribes in the Eastern Highlands of New Guinea. Uniform topographical central nervous system histopathology includes spongiform change and neuronal loss, with amyloid (kuru) plaques in approximately 75% of cases.     

Can prion-like propagation occur in neurodegenerative diseases?: in view of transmissible systemic amyloidosis

Common neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are now considered as "protein misfolding diseases," because the misfolding of a small number of proteins is a key event in the pathogenesis and progression of these diseases. Proteins that are prone to misfolding and thereby associated with neurodegenerative diseases include amyloid β (AD), tau (AD and tauopathy), α-synuclein (PD, dementia with Lewy bodies, etc.), polyglutamine proteins (Huntington's disease, spinocerebellar ataxia, etc.), and superoxide dismutase 1 (amyotrophic lateral sclerosis). These proteins share certain essential properties with prions. Similar to abnormal prions, misfolded proteins function as a template to catalyze the misfolding of the native proteins and assemble into insoluble, β-sheet-rich, fibrillar aggregates termed as "amyloids." Furthermore, there is enough evidence supporting the intercellular transfer of misfolded protein aggregates. The transmission of these aggregates from one cell to another may be in accordance with the concept that neuropathological changes propagate along neuronal circuits in neurodegenerative diseases. Prion-like propagation mechanisms have been extensively analyzed in connection with systemic amyloidoses such as amyloid A (AA) amyloidosis and amyloid apolipoprotein AII (AApoAII) amyloidosis. Studies have shown that AA and AApoAII amyloidoses are transmitted from one organism to another through amyloid fibrils. However, studies have not yet proved that protein misfolding diseases, except for prion diseases, are infectious. Given the intercellular transfer of misfolded protein aggregates, we cannot ignore the possibility that disease-specific, misfolded proteins can be transmitted between individuals through surgical procedures or tissue transplantation. Importantly, cell non-autonomous mechanisms underlying the pathogenesis of neurodegenerative diseases may represent a more readily accessible target for novel disease-modifying therapies. In the present review, we discuss some aspects of the prion-like propagation of neurodegenerative diseases, taking into consideration the accumulated evidence supporting the transmissibility of systemic amyloidoses.     

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.     

Volume transmission-mediated encephalopathies: a possible new concept?

There is strong evidence that the composition of cerebrospinal fluid (CSF) influences brain development, neurogenesis, and behavior. The bidirectional exchange of CSF and interstitial fluid (ISF) across the ependymal and pia-glial membranes is required for these phenomena to occur. Because ISF surrounds the parenchymal compartment, neuroactive substances in the CSF and ISF can influence neuronal activity. Functionally important neuroactive substances are distributed to distant sites of the central nervous system by the convection and diffusion of CSF and ISF, a process known as volume transmission. It has recently been shown that pathologically altered CSF from patients with acute traumatic brain injury suppresses in vitro neuronal network activity (ivNNA) recorded by multielectrode arrays measuring synchronously bursting neural populations. Functionally relevant substances in pathologically altered CSF have been biochemically identified, and ivNNA has been partially recovered by pharmacologic intervention. It remains unclear whether the in vivo parenchymal compartment remains unaffected by pathologically altered CSF that significantly impairs ivNNA. We hypothesize that pathologic CSF alterations are not just passive indicators of brain diseases but that they actively and directly evoke functional disturbances in global brain activity through the distribution of neuroactive substances, for instance, secondary to focal neurologic disease. For this mechanism, we propose the new term volume transmission-mediated encephalopathies (VTE). Recording ivNNA in the presence of pure human CSF could help to identify and monitor functionally relevant CSF alterations that directly result in VTEs, and the collected data might point to therapeutic ways to antagonize these alterations.     

What is the basis of transmissible spongiform encephalopathy induced neurodegeneration and can it be repaired?

Once an animal becomes infected with a prion disease, or transmissible spongiform encephalopathy (TSE), the progression of infection is relentless and inevitably fatal, although often with such prolonged incubation periods that an alternative cause of death can intervene. Infection has been compared to 'setting a clock' which then runs inexorably as the disease spreads, usually through the lymphoreticular system and then via peripheral nerves to the central nervous system (CNS), although the mechanism controlling the protracted progression is not known. Clinical disease develops as characteristic degenerative changes in the CNS progress, but the molecular basis for this pathology is not clear, particularly the relationship between the deposition of abnormal PrP and neuronal dysfunction. Recent research has identified several means of slowing (if not stopping) the clock when infection has not yet reached the CNS; although the potential for later stage therapies seems limited, neuroprotective strategies which have been shown to be effective in other neurodegenerative conditions may also ameliorate TSE induced CNS pathology. This review focuses on our current knowledge of the key events following infection of the CNS and the opportunities for intervention once the CNS has become infected.     

Neurological diseases and risk of suicide attempt: a case–control study

Introduction

Neurological diseases have a profound impact on quality of life. We investigated the risk of suicide attempt in ten neurological diseases.

Methods

Case–control study. Cases were identified from the Danish Poison Information Centre database in the period 2006–2013. The prevalence of ten neurological diagnoses was compared with the prevalence in a randomly sampled age- and gender-matched control group.

Results

We identified 8974 cases of suicidal attempt and 89,740 controls. We found an association between suicide attempt in nine of ten neurological diseases and disease groups, including stroke [odds ratio (OR) 3.1, 95% confidence interval (CI) (2.8–3.6)], Huntington’s disease [OR 8.8, 95% CI (3.2–24.1)], amyotrophic lateral sclerosis [OR 5.0, 95% CI (1.7–14.6)], Parkinson’s disease [OR 2.9, 95% CI (1.8–4.6)], Alzheimer’s disease and other degenerative diseases [OR 4.8, 95% CI (3.1–7.5)], multiple sclerosis [OR 1.5, 95% CI (1.1–2.1)], epilepsy [OR 4.5, 95% CI (4.1–5.0)], hereditary and idiopathic neuropathy [OR 2.2, 95% CI (1.1–4.3)] and myasthenia gravis [OR 4.3, 95% CI (2.0–9.4)].

Conclusion

Nine out of ten chronic neurological diseases were associated with an increased risk of suicide attempt. These data must be considered for clinicians treating this vulnerable group of patients.

     

Systemic autoimmune diseases are associated with an increased risk of obsessive–compulsive disorder: a nationwide population-based cohort study

Social Psychiatry and Psychiatric Epidemiology - Studies suggested autoimmunity plays a role in the etiology of obsessive–compulsive disorder (OCD). The purpose of this study was to determine...     

Young blood products:emerging treatment for Alzheimer's disease?

Alzheimer's disease is the most common neurodegenerative disorder and no disease-modifying treatment is currently available.Research has shown that while brain neurogenesis continues in adult life,it declines with age.Using parabiosis,plasma transfusions and direct administration of neural growth factors,animal studies have demonstrated the positive impact of exposure to young blood products on neurogenesis and synaptic plasticity in an aging brain.The hippocampus and the sub-ventricular zones were identified as the main regions affected.Promising findings have prompted researchers to experiment their effects in subjects with an established neurocognitive disorder,such as Alzheimer's disease.They argued that modification of brain vasculature,reactivation of adult neural stem cells,and remodeling of their synaptic activity/plasticity may lead to cognitive enhancement and increased neurogenesis.One pilot human study found that young donor plasma infusion protocols for adults with Alzheimer's disease were safe and feasible;however,no statistically significant improvements in cognition were detected.There is a need to conduct additional placebo-controlled human studies in larger samples.Future studies should focus on identifying an optimal age at which an intervention in humans may yield significant cognitive enhancement,as well as determining the types of transfusions with the best efficacy and tolerability profiles.     

Evaluation of α-synuclein as a novel cerebrospinal fluid biomarker in different forms of prion diseases

Introduction

Accurate diagnosis of prion diseases and discrimination from alternative dementias gain importance in the clinical routine, but partial overlap in cerebrospinal fluid (CSF) biomarkers impedes absolute discrimination in the differential diagnostic context.

Alzheimer’s disease:a tale of two diseases?

Sporadic late-onset Alzheimer’s disease(SLOAD)and familial early-onset Alzheimer’s disease(FEOAD)associated with dominant mutations in APP,PSEN1 and PSEN2,are thought to represent a spectrum of the same disorder based on near identical behavioral and histopathological features.Hence,FEOAD transgenic mouse models have been used in past decades as a surrogate to study SLOAD pathogenic mechanisms and as the gold standard to validate drugs used in clinical trials.Unfortunately,such research has yielded little output in terms of therapeutics targeting the disease’s development and progression.In this short review,we interrogate the widely accepted view of one,dimorphic disease through the prism of the Bmi1+/–mouse model and the distinct chromatin signatures observed between SLOAD and FEOAD brains.     

Daytime napping and increased risk of incident respiratory diseases: symptom,marker, or risk factor?

BackgroundWe have identified a strong association between daytime napping and increased mortality risk from respiratory diseases, but little is known about the relationship between daytime napping and respiratory morbidity.MethodsData were drawn from the European Prospective Investigation into Cancer and Nutrition-Norfolk cohort. Participants reported napping habits during 1998–2000 and were followed up for respiratory disease hospital admissions until March 2009. Cox proportional hazards regression was used to examine the association between daytime napping and respiratory disease incidence risk.ResultsThe study sample included 10,978 men and women with a mean age of 61.9 years, and a total of 946 incident respiratory disease cases were recorded. After adjustment for age, sex, social class, education, marital status, employment status, nightshift work, body mass index, physical activity, smoking, alcohol intake, self-reported general health, hypnotic drug use, habitual sleep duration, and preexisting health conditions, daytime napping was associated with an increase in the overall respiratory disease incidence risk (hazard ratio (HR) = 1.32, 95% confidence interval (CI) 1.15, 1.52 for napping <1 h; HR = 1.54, 95% CI 1.14, 2.09 for napping ≥1 h). This association was more pronounced for lower respiratory diseases, especially for the risk of chronic lower respiratory diseases (HR = 1.52, 95% CI: 1.18, 1.96 for napping <1 h; HR = 1.72, 95% CI: 1.01, 2.92 for napping ≥1 h, overall p = 0.003).ConclusionsExcessive daytime napping might be a useful marker of future respiratory disease incidence risk. Further studies are required to confirm these findings and help understand potential mechanisms.