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Here we demonstrate that a guanine-to-adenine substitution within guanine repeat sequences in the MSH 5′-UTR weakens G-quadruplex stability, leading to increased protein synthesis. The abnormal pro...

La glycosylation est l’une des modifications essentielles des protéines et des lipides. Elle s’effectue principalement dans le réticulum endoplasmique et l’appareil de Golgi et fait appel à une machinerie moléculaire spécifique, associant plusieurs centaines de glycosyltransférases, de glycosidases, de transporteurs et de protéines régulatrices. Des modifications de la glycosylation sont retrouvées dans certaines maladies, notamment dans les cancers. Ces altérations peuvent affecter toutes les formes de glycosylation réticulaires et/ou golgiennes, et conduire à des dysfonctionnements du métabolisme cellulaire. Dans cette revue, nous présentons l’état actuel des connaissances des mécanismes de la glycosylation. Nous illustrerons, au travers d’exemples représentatifs, comment l’altération de certains de ces mécanismes de régulation peut affecter les différentes formes de glycosylation des protéines et des lipides et participer au développement des cancers.

In diabetic patients, diabetic retinopathy (DR) is the leading cause of blindness and seriously affects the quality of life. However, current treatment methods of DR are not satisfactory. Advances have been made in understanding abnormal protein interactions and signaling pathways in DR pathology, but little is known about epigenetic regulation. Non-coding RNAs, such as circular RNAs (circRNAs), have been shown to be associated with DR. In this review, we summarized the function of circRNAs and indicated their roles in the pathogenesis of DR, which may provide new therapeutic targets for clinical treatment.

Sustaining neuronal proteostasis during the course of our life is a central aspect required for brain function. The dynamic nature of synaptic composition and abundance is a requisite to drive cognitive and motor processes involving a tight control of many aspects of protein biosynthesis and degradation. Through the concerted action of specialized stress sensors, the proteostasis network monitors and limits the accumulation of damaged, misfolded, or aggregated proteins. These stress pathways signal to the cytosol and nucleus to reprogram gene expression, enabling adaptive programs to recover cell function. During aging, the activity of the proteostasis network declines, which may increase the risk of accumulating abnormal protein aggregates, a hallmark of most neurodegenerative diseases. Here, I discuss emerging concepts illustrating the functional significance of adaptive signaling pathways to normal brain physiology and their contribution to age-related disorders. Pharmacological and gene therapy strategies to intervene and boost proteostasis are expected to extend brain healthspan and ameliorate disease states.

Neurodegenerative disorders emerge from the failure of intricate cellular mechanisms, which ultimately lead to the loss of vulnerable neuronal populations. Research conducted across several laboratories has now provided compelling evidence that pathogenic proteins can also contribute to non-cell autonomous toxicity in several neurodegenerative contexts, including Alzheimer’s, Parkinson’s, and Huntington’s diseases as well as Amyotrophic Lateral Sclerosis. Given the nearly ubiquitous nature of abnormal protein accumulation in such disorders, elucidating the mechanisms and routes underlying these processes is essential to the development of effective treatments. To this end, physiologically relevant human in vitro models are critical to understand the processes surrounding uptake, release and nucleation under physiological or pathological conditions. This review explores the use of human-induced pluripotent stem cells (iPSCs) to study prion-like protein propagation in neurodegenerative diseases, discusses advantages and limitations of this model, and presents emerging technologies that, combined with the use of iPSC-based models, will provide powerful model systems to propel fundamental research forward.

Abnormal protein aggregation in the nervous tissue leads to several neurodegenerative disorders like Alzheimer's disease (AD). In AD, accumulation of the amyloid beta (Aβ) peptide is proposed to be an early important event in pathogenesis. Significant research efforts are devoted so as to understand the Aβ misfolding and aggregation. Molecular dynamics (MD) simulations complement experiments and provide structural information at the atomic level with dynamics without facing the same experimental limitations. Artificial missense mutations are employed experimentally and computationally for providing insights into the structure-function relationships of amyloid-β in relation to the pathologies of AD. Present work describes the MD simulations for 100 ns so as to probe the structural and conformational dynamics of Aβ1-42 assemblies and its mutants. Essential dynamics analysis with respect to conformational deviation of

International audience; Deux voies de dégradation des protéines mal repliées sont classiquement décrites : la voie du protéasome et la voie de l’autophagie. Nous décrivons ici une nouvelle voie de protéostase cellulaire ne dégradant pas la protéine anormale mais l’expulsant hors de la cellule grâce à des nanovésicules appelées myélinosomes. Ces myélinosomes sont produits par la cellule dans des situations pathologiques ou de stress en lien avec des facteurs génétiques ou environnementaux. Sur le plan morphologique, les myélinosomes sont caractérisés par des membranes osmiophiles denses aux électrons dont l’arrangement empilé est semblable à celui de la myéline et présente jusqu’à 30 feuillets selon le type de cellule. Dans deux modèles, au moins, de maladies génétiques (la maladie de Huntington et la mucoviscidose), les myélinosomes sont importants pour éliminer les protéines mutées par un processus sécrétoire inhabituel, évitant ainsi leur agrégation dans les cellules.

Alpha1-antitrypsin deficiency (A1ATD) is an inherited cause of chronic liver disease. It is inherited in an autosomal codominant pattern with each inherited allele expressed in the formation of the final protein, which is primarily produced in hepatocytes. The disease usually occurs in pediatric and elderly populations. The disease occurs with the accumulation of abnormal protein polymers within hepatocytes that can induce liver injury and fibrosis. It is a commonly under-recognized and underdiagnosed condition. Patients diagnosed with the disease should be regularly monitored for the development of liver disease. Liver transplant is of proven benefit in A1ATD liver disease.

Membraneless organelles (MLOs) present as a condensed metastable phase of different proteins and RNAs organized via liquid–liquid phase separation. Recent evidence suggests the extensive incorporation of molecular chaperones into the dynamic assembly of MLOs, where different chaperones coordinate to spatiotemporally maintain the protein homeostasis and avoid abnormal protein aggregation.

Background Ion-selective electrodes (ISE) have become the mainstay of electrolyte measurements in the clinical laboratory. In most automated analyzers used in large diagnostic laboratories, indirect ISE (iISE) -based electrolyte estimation is done; whereas direct ISE (dISE) -based equipment are mostly used in blood gas analyzers and in the point-of-care (PoC) setting. Content Both the techniques, iISE as well as dISE, are scientifically robust; however, the results are often not interchangeable. Discrepancy happens between the two commonly due to interferences that affect the two measuring principles differently. Over the last decade, several studies have reported discrepancies between dISE and iISE arising due to abnormal protein and lipid contents in the sample. Summary The present review endeavors to consolidate the knowledge accumulated in relation to interferences due to abnormal protein and lipid contents in sample with the principal focus resting on probable solutions thereof.

Abnormal protein aggregation has been linked to many neurodegenerative diseases, including Parkinson’s disease (PD). The main pathological hallmark of PD is the formation of Lewy bodies (LBs) and Lewy neurites, both of which contain the presynaptic protein alpha-synuclein (α-syn). Under normal conditions, native α-syn exists in a soluble unfolded state but undergoes misfolding and aggregation into toxic aggregates under pathological conditions. Toxic α-syn species, especially oligomers, can cause oxidative stress, membrane penetration, synaptic and mitochondrial dysfunction, as well as other damage, leading to neuronal death and eventually neurodegeneration. Early diagnosis and treatments targeting PD pathogenesis are urgently needed. Given its critical role in PD, α-syn is an attractive target for the development of both diagnostic tools and effective therapeutics. This review summarizes the progress toward discovering imaging probes and aggregation inhibitors for α-syn. Relevant strategies and techniques in the discovery of α-syn-targeted drugs are also discussed.

Significance Lewy bodies (LBs), which mainly consist of α-syn, are neuropathological hallmarks of patients with Parkinson’s disease (PD). Recently, it has been reported that aggregates of α-syn with cross-β structures are capable of propagating within the brain in a prionlike manner. However, there is still no evidence that such propagation occurs in the patient’s brain. Here, we examined LBs in thin sections of autopsy brains of patients with PD using microbeam X-ray diffraction (XRD) and confirmed that aggregates of α-syn with a cross-β structure exist in brains of PD patients. Our finding supports the concept that PD is a type of amyloidosis, a disease featuring the accumulation and propagation of amyloid fibrils of α-syn., Many neurodegenerative diseases are characterized by the accumulation of abnormal protein aggregates in the brain. In Parkinson’s disease (PD), α-synuclein (α-syn) forms such aggregates called Lewy bodies (LBs). Recently, it has been reported that aggregates of α-syn with a cross-β structure are capable of propagating within the brain in a prionlike manner. However, the presence of cross-β sheet-rich aggregates in LBs has not been experimentally demonstrated so far. Here, we examined LBs in thin sections of autopsy brains of patients with PD using microbeam X-ray diffraction (XRD) and found that some of them gave a diffraction pattern typical of a cross-β structure. This result confirms that LBs in the brain of PD patients contain amyloid fibrils with a cross-β structure and supports the validity of in vitro propagation experiments using artificially formed amyloid fibrils of α-syn. Notably, our finding supports the concept that PD is a type of amyloidosis, a disease featuring the accumulation of amyloid fibrils of α-syn.

Recent studies in neurodegenerative conditions have increasingly highlighted that the same neuropathology can trigger different clinical phenotypes or, vice-versa, that similar phenotypes can be triggered by different neuropathologies. This evidence has called for the adoption of a pathology spectrum-based approach to study neurodegenerative proteinopathies. These conditions share brain deposition of abnormal protein aggregates, leading to aberrant biochemical, metabolic, functional, and structural changes. Positron emission tomography (PET) is a well-recognized and unique tool for the in vivo assessment of brain neuropathology, and novel PET techniques are emerging for the study of specific protein species. Today, key applications of PET range from early research and clinical diagnostic tools to their use in clinical trials for both participants screening and outcome evaluation. This position article critically reviews the role of distinct PET molecular tracers for different neurodegenerative proteinopathies, highlighting their strengths, weaknesses, and opportunities, with special emphasis on methodological challenges and future applications. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Background: Detection of tumor abnormal protein (TAP) is a recently developed but not widely used method for screening malignancies. This study is aimed to assess the ability of TAP level in distinguishing solid malignancies. Methods: The TAP levels were compared between malignancies and benign disease patients, and the distinguish ability were evaluated by receiver operating characteristic (ROC) curve analysis. We further analyzed TAP levels in physical examination populations with different genders and age， and compared clinical parameters in TAP positive and negative groups. Results: We found that TAP levels were getting higher from benign to precancerous lesions and to malignancies, and TAP levels were decreased after tumor resection. ROC curve analysis showed that TAP levels might aid to distinguish between malignancies and benign diseases. In the physical examination populations, the positive ratio of TAP was 3.7% (4.6% to female and 3.1% to male), and the TAP levels were higher in female. The TAP levels in populations above 60 year age were higher than those in less than 60 years, which increased with age. The hemoglobin levels were lower in TAP positive populations. Conclusion: TAP was an effective biomarker of screening and following-up for malignancies. There may be some potential links between TAP and hemoglobin, which deserve further studies.

The evolutionary theory of aging has set the foundations for a comprehensive understanding of aging. The biology of aging has listed and described the “hallmarks of aging,” i.e., cellular and molecular mechanisms involved in human aging. The present paper is the first to infer the order of appearance of the hallmarks of bilaterian and thereby human aging throughout evolution from their presence in progressively narrower clades. Its first result is that all organisms, even non-senescent, have to deal with at least one mechanism of aging – the progressive accumulation of misfolded or unstable proteins. Due to their cumulation, these mechanisms are called “layers of aging.” A difference should be made between the first four layers of unicellular aging, present in some unicellular organisms and in all multicellular opisthokonts, that stem and strike “from the inside” of individual cells and span from increasingly abnormal protein folding to deregulated nutrient sensing, and the last four layers of metacellular aging, progressively appearing in metazoans, that strike the cells of a multicellular organism “from the outside,” i.e., because of other cells, and span from transcriptional alterations to the disruption of intercellular communication. The evolution of metazoans and eumetazoans probably solved the problem of aging along with the problem of unicellular aging. However, metacellular aging originates in the mechanisms by which the effects of unicellular aging are kept under control – e.g., the exhaustion of stem cells that contribute to replace damaged somatic cells. In bilaterians, additional functions have taken a toll on generally useless potentially limited lifespan to increase the fitness of organisms at the price of a progressively less efficient containment of the damage of unicellular aging. In the end, this picture suggests that geroscience should be more efficient in targeting conditions of metacellular aging rather than unicellular aging itself.

Ming Zhang,* Xiaoyu Wang,* Zhenghua Wang Department of Gastrointestinal Oncology (Ward I), The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 121000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhenghua WangDepartment of Gastrointestinal Oncology (Ward I), The First Affiliated Hospital of Jinzhou Medical University, No. 2, Section 5, Renmin Street, Jinzhou, Liaoning, 121000, People’s Republic of ChinaEmail wangzhenghua1977@163.comObjective: To study the correlation between tumor abnormal protein (TAP) and tumor markers, blood glucose, uric acid and coagulation function in gastric adenocarcinoma and to evaluate the clinical application of TAP in the diagnosis of gastric adenocarcinoma.Methods: A total of 34 nontumor patients and 95 gastric adenocarcinoma patients admitted to the First Affiliated Hospital of Jinzhou Medical University were enrolled in this study. Fresh blood from patients’ fingertips was collected, all blood samples were examined with TAP testing kit, and then searched and measured the condensed particulate matter.Results: The comparison of TAP between nontumor patients and gastric adenocarcinoma patients was statistically significant (P< 0.05). Bivariate correlation analysis was conducted between TAP and other related tumor markers (alpha-fetoprotein, carcinoembryonic antigen, carbohydrate antigen 19– 9 (CA199), carbohydrate antigen 72– 4 (CA72-4)), blood glucose, uric acid, and coagulation function-related indicators, and the results showed that the correlation between TAP and CA199, CA72-4, and activated partial prothrombin time was statistically significant. In addition, according to the analysis results, there was no significant difference among TAP and age, height and weight in the tumor population and the nontumor population.Conclusion: TAP can be used for the screening and diagnosis of gastric adenocarcinoma, and the effect of TAP combined with other indicators is more significant than TAP alone.Keywords: tumor abnormal protein, gastric adenocarcinoma, tumor markers, blood glucose, uric acid, coagulation function

Poly(ADP-ribose) (PAR) is an RNA-like polymer that regulates an increasing number of biological processes. Dysregulation of PAR is implicated in neurodegenerative diseases characterized by abnormal protein aggregation, including Amyotrophic Lateral Sclerosis (ALS). PAR forms condensates with FUS, an RNA-binding protein linked with ALS, through an unknown mechanism. Here, we demonstrate that a strikingly low concentration of PAR (1 nM) is sufficient to trigger condensation of FUS near its physiological concentration (1 µM), which is three orders of magnitude lower than the concentration at which RNA induces condensation (1 µM). Unlike RNA, which associates with FUS stably, PAR interacts with FUS transiently, triggering FUS to oligomerize into condensates. Moreover, inhibition of a major PAR-synthesizing enzyme, PARP5a, diminishes FUS condensation in cells. Despite their structural similarity, PAR and RNA co-condense with FUS, driven by disparate modes of interaction with FUS. Thus, we uncover a mechanism by which PAR potently seeds FUS condensation.

Purpose of review This review discusses recent developments in the application of magnetic particle imaging (MPI) to dementia research. Recent findings MPI is a tracer method that is currently in the preclinical development stage. It provides high sensitivity for the detection and localization of magnetic nanoparticles with very high spatial and temporal resolution and a similar application spectrum as PET. Unlike MRI, the MPI signal is not contaminated by background signal from tissues and is highly quantifiable in terms of local tracer concentrations. These properties make the technology ideally suited for localization of specific targets or quantification of vascular parameters. MPI uses magnetic nanoparticles which can be modified by various coatings, and by adding ligands (i.e. peptides or antibodies) for specific targeting. This makes MPI an attractive tool for the potential detection of abnormal protein deposits, such as Aβ plaques, with greater specificity than MRI. Neural stem cells can also be labelled with these nanoparticles ex vivo to monitor their migration in vivo. Summary The capabilities of MPI opens the potential for several applications of MPI in neurocognitive disorders, including vascular imaging, detection of amyloid plaques and potentially other pathological hallmarks of Alzheimer's disease and stem-cell tracking.

The number of people with dementia is increasing rapidly due to the increase in the aging population. Alzheimer’s disease (AD) is a type of neurodegenerative dementia caused by the accumulation of abnormal proteins. Genetic mutations, smoking, and several other factors have been reported as causes of AD, but alterations in glycans have recently been demonstrated to play a role in AD. Amyloid-β (Aβ), a cleaved fragment of APP, is the source of senile plaque, a pathological feature of AD. APP has been reported to undergo N- and O-glycosylation, and several Polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-Ts) have been shown to have catalytic activity for the transfer of GalNAc to APP. Since O-glycosylation in the proximity of a cleavage site in many proteins has been reported to be involved in protein processing, O-glycans may affect the cleavage of APP during the Aβ production process. In this report, we describe new findings on the O-glycosylation of APP and Aβ production.

Amyloidosis is a rare multisystem disease due to deposition of abnormal protein fragments, and cardiac amyloidosis is progressive and difficult to diagnose due to its subtle and non-specific symptoms unless the physician maintains a high degree of suspicion. This case report focuses on amyloid deposition in the heart of an 84-year-old woman who presented with symptoms of uncompensated heart failure.

Abnormal aggregation of proteins into filamentous aggregates commonly associates with many diseases, such as Alzheimer’s disease, Parkinson’s disease and type-2 diabetes. These filamentous aggregates, also known as amyloids, can propagate their abnormal structures to either the same precursor molecules (seeding) or other protein monomers (cross-seeding). Cross-seeding has been implicated in the abnormal protein aggregation and has been found to facilitate the formation of physiological amyloids. It has risen to be an exciting area of research with a high volume of published reports. In this review article, we focus on the biophysical processes underlying the cross-seeding for some of the most commonly studied amyloid proteins. Here we will discuss the relevant literature related to cross-seeded polymerization of amyloid-beta, human islet amyloid polypeptide (hIAPP, or also known as amylin) and alpha-synuclein. SEVI (semen-derived enhancer of viral infection) amyloid formation by the cross-seeding between the bacterial curli protein and PAP(248–286) is also briefly discussed.

This chapter defines normal memory and cognitive impairment. Different types of memory are described with mechanism of memory formation and forgetfulness. It then traces how Dr Alzheimer described his first patient over 100 years ago, and the abnormal proteins in her brain (now known as plaques and tangles) the hallmarks of Alzheimer’s disease. There is a section on the classification of dementia followed by the prevalence and risk factors for developing Alzheimer’s disease in old age.

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and polyglutamine diseases are caused by aggregation and abnormal accumulation of the disease-causative proteins in brain and spinal cord. Recent studies have suggested that proteins associated with neurodegenerative diseases are secreted and transmitted intercellularly via extracellular vesicles, which may be involved in propagation of abnormal protein accumulation and progressive degeneration in patient brains. On the other hand, it has been also reported that extracellular vesicles have neuroprotective roles in these diseases, which potentially contribute to preventing aggregation formation and aberrant accumulation of the disease-associated proteins. In this review, I summarize the current understanding of the roles of extracellular vesicles in neurodegenerative diseases, especially focusing on the pathogenic and neuroprotective aspects. Elucidation of these two aspects of extracellular vesicles would provide insight into not only potential therapeutic targets for treatment of neurodegenerative diseases but also development of extracellular vesicle-based biomarkers for disease diagnostics.

Background: Esophageal squamous cell carcinoma (ESCC) acts as a fatal malignant tumor among human beings and is marked by late-stage diagnosis, frequent recurrence, metastasis, and therapy resistance. Tumor abnormal protein (TAP) remarkably affects cancer development and progression of human cancers. TAP has been shown to be a biomarker for gastric and lung cancer progression. Nevertheless, the clinical value exhibited by TAP for ESCC has not been well-explained in the current literature.Methods: The present study included 183 ESCC cases who received surgical resection and 183 cases who had normal physical checkup from March 2013 to January 2015 at the People's Hospital of Chizhou, and used the TAP detection agent for evaluating the TAP relative level.Results: As found, ESCC patients presented an obviously higher TAP expression relative to cases who had normal physical checkup. Moreover, TAP expression was significantly downregulated after surgery. Furthermore, the TAP expression was correlated with gender, smoking, pathologic differentiation, and pN stage, but not with age, tumor location, surgical type, pT stage, and vascular invasion. High expression of TAP was significantly correlated with poorer overall survival (OS) rate in ESCC patients. TAP was an independent prognostic predictor in ESCC patients, based on the multivariate survival analysis.Conclusion: The study reveals how TAP upregulation promotes ESCC malignant progression, and concludes that TAP acts as the therapeutic target and potential biomarker specific to ESCC.

According to current paradigms, various risk factors, such as genetic mutations, oxidative stress, neural network dysfunction, and abnormal protein degradation, contribute to the progression of brain disorders. Through the cooperation of gene transcripts in biological processes, the study of noncoding RNAs can lead to insights into the cause and treatment of brain disorders. Recently, long noncoding RNAs (lncRNAs) which are longer than 200 nucleotides in length have been suggested as key factors in various brain disorders. Accumulating evidence suggests the potential of lncRNAs as diagnostic or prognostic biomarkers and therapeutic targets. High-throughput screening-based sequencing has been instrumental in identification of lncRNAs that demand new approaches to understanding the progression of brain disorders. In this review, we discuss the recent progress in the study of lncRNAs, and addresses the pathogenesis of brain disorders that involve lncRNAs and describes the associations of lncRNAs with neurodegenerative disorders such as Alzheimer disease (AD), Parkinson disease (PD), and neurodevelopmental disorders. We also discuss potential targets of lncRNAs and their promise as novel therapeutics and biomarkers in brain disorders.

Abnormal protein aggregation has been intensively studied for over 40 years and broadly discussed in the literature due to its significant role in neurodegenerative diseases etiology. Structural reorganization and conformational changes of the secondary structure upon the aggregation determine aggregation pathways and cytotoxicity of the aggregates, and therefore, numerous analytical techniques are employed for a deep investigation into the secondary structure of abnormal protein aggregates. Molecular spectroscopies, including Raman and infrared ones, are routinely applied in such studies. Recently, the nanoscale spatial resolution of tip-enhanced Raman and infrared nanospectroscopies, as well as the high sensitivity of the surface-enhanced Raman spectroscopy, have brought new insights into our knowledge of abnormal protein aggregation. In this review, we order and summarize all nano- and micro-spectroscopic marker bands related to abnormal aggregation. Each part presents the physical principles of each particular spectroscopic technique listed above and a concise description of all spectral markers detected with these techniques in the spectra of neurodegenerative proteins and their model systems. Finally, a section concerning the application of multivariate data analysis for extraction of the spectral marker bands is included.

Congenital myasthenic syndrome (CMS) is a heterogenous group of inherited disorders caused by genetic defects that affect transmission of signals from nerve terminals to muscle endplates at the neuromuscular junction (NMJ) [1–4]. Based on the site and biochemical mechanism of the underlying defect, they are classified in presynaptic, synaptic (basal lamina-associated), and postsynaptic subcategories of CMS. The recent classification takes into account defects in protein glycosylation causing CMS [2]. These abnormal proteins are located at different sites of the endplate.

Neurodegenerative diseases are one of the most serious health and social problems in the world today. Abnormal protein aggregation is responsible for the etiology of these diseases, and it is of central importance to many research disciplines. A better understanding of abnormal protein aggregation mechanisms may determine strategies for the treatment. A very promising alternative for commonly used analytical techniques is an application of molecular nanospectroscopy, such as tip-enhanced Raman (TER), nano-Fourier-transform infrared, and atomic force microscopy–infrared spectroscopies in studies of abnormal aggregation of neurodegenerative peptides. These techniques may probe nanovolumes of investigated samples and therefore they allow for chemical/structural analysis of individual aggregates in very inhomogeneous samples of aggregating peptide. Prior theoretical and experimental approaches allowed modeling of hypothetic aggregation pathways. However, methodological limitations prevented direct experimental observations. Deep analysis of the secondary structure of single peptide aggregates brought new insights into our knowledge of possible aggregation schemes. Above all, an application of nanospectroscopic techniques extended existing knowledge about cytotoxic protein aggregation and understanding, at the molecular level, of the influence of intrinsic and extrinsic factors on the aggregation processes. Such knowledge is essential for developing effective therapeutic strategies, which inhibit self-assembly.

Investigation of disease-specific biomarkers has the potential to advance the understanding of what causes Parkinson's disease (PD) and can lead to discovery of better treatments. Although PD's clinical features can be unmistakable, current laboratory methods have not enhanced its recognition. Over several decades, many attempts have sought out potential neurochemical indicators of PD diagnosis and progression. A logical starting point for this search has been cerebrospinal fluid (CSF), a biospecimen contiguous with the brain sites of pathology in this disorder. Guiding the search for biomarkers has been an understanding that neurons undergoing degeneration manifest distinct physiological changes such as abnormal protein aggregation, altered mitochondrial function, and a decline in neurotransmitter output. Beyond targeted searches for PD biomarkers, some studies have taken an exploratory approach by profiling large numbers of CSF constituents in the hopes of a successful discovery. This chapter will review the highlights of several decades of investigation into CSF PD biomarkers.

Introduction: The detection of abnormal protein bands (APB) different from the original monoclonal protein in patients with multiple myeloma (MM) who underwent stem cell transplantation and/or chemotherapy has been reported. These atypical serum immunofixation patterns may be monoclonal (also termed secondary monoclonal gammopathy of undetermined significance) or oligoclonal bands (OB). The prognostic significance of this phenomenon remains controversial. This systematic review and meta-analysis aimed to summarize and analyze the evidence for the association between APB with survival in MM patients. Methods: A systematic search of PubMed, Cochrane, Google Scholar, Medline-Ovid, CINAHL, and ERIC, was conducted using relevant search terms. All studies were screened using predefined selection criteria and critically appraised for quality assessment following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. All studies that described the presence of APB, defined as monoclonal spike with heavy or light chain immunoglobulin distinct from the original paraprotein at initial diagnosis of MM, and its associations with survival were included. Studies that reported multivariate adjusted hazard ratios (HR) were further included for meta-analysis. Random-effects model was used to synthesize the pooled HR estimate for the association of APB with survival. Cochran's Q statistics and I2 tests were used to evaluate statistical heterogeneity. Results: A total of 24 out of 181 eligible studies were included for qualitative synthesis. Four studies (including 1115 patients) that reported HR estimates were included in the final meta-analysis. The random-effect summary HR for the progression-free survival among patients with APB was 0.44 (95% CI, 0.31-0.65) with no statistical heterogeneity (I2=0%, p=0.93). The pooled HR for the association with overall survival was 0.31 (95% CI, 0.14-0.66) with moderate statistical heterogeneity (I2=45%; p=0.16) for patients with APB. One study (Silva et al, 2017) only included patients with at least very good partial response while the other three studies reported similar findings of higher occurrence of APB with complete response (Tovar et al, 2013; Jo et al, 2014; Zou et al, 2014). These results are also consistent with the presumed association of APB with complete response as suggested in other studies included in qualitative review. Conclusions: This study indicated a potential prognostic value of APB for favorable outcomes in the context of both overall and progression-free survival in MM patients after treatment. Further research is needed to evaluate the prognostic impact of the sole emergence of APB irrespective of treatment response. Figure 1 Figure 1. Disclosures Jamshed: Takeda: Honoraria.

Objectives To investigate the words and descriptions used by haematology healthcare professionals (HCPs) to describe monoclonal gammopathy of undetermined significance (MGUS) to their patients. Methods A cross-sectional survey of haematology HCPs attending an annual haematology conference was undertaken. Content analysis was applied to the returned qualitative responses. Results In total, 55 people, many of whom were doctors (n=32; 58.2%) responded. The majority of respondents reported using simple terminology such as ‘abnormal protein’ to describe MGUS to their patients. Some reported using analogies that the patient was more likely to be familiar with, such as comparing a paraprotein to the finding of a mole or lump. Education level, age and cognitive ability were cited as important factors in deciding how and if information was relayed to patients. Many respondents supported frequent follow-up and the transfer of low risk MGUS patients to primary care. However, several highlighted a lack of awareness and understanding of MGUS outside of haematology, particularly within primary care. Only 41.8% of respondents reported providing all of their patients with an information leaflet. Conclusions With an ageing population, it is important to consider management strategies for MGUS patients. Our findings will assist those in making these arrangements. This article is protected by copyright. All rights reserved.

Familial amyloidosis of the Finnish type or Meretoja syndrome is a rare autosomic dominant inherited systemic condition. It was first described by Meretoja in Finland in 1969. It is a disease produced by a single mutation in the gene coding for gelsolin, which generates an abnormal protein that cumulates in tissues and leads to various signs. Obtaining an early diagnosis can be challenging, as the first manifestations of the disease are ophthalmological and may only be seen with slit-lamp biomicroscopy. We present the first 3 cases diagnosed in Argentina, confirmed by genetic molecular testing.

Powerful AAA+ biological nanomachines, such as ClpY, form hexameric ring structures, which selectively process abnormal proteins targeted for degradation by unfolding and threading them through a narrow central channel. The molecular details of this process are not yet fully understood. We perform Langevin dynamics simulations using a coarse-grained model of substrate proteins (SPs), Titin I27 and its V13P variant, threading through the ClpY pore. We probe the effect of ClpY surface heterogeneity and changes in pore width on SP orientation and the direction of applied force during SP unfolding. We contrast mechanisms of SP unfolding in a restrained geometry, as in single-molecule force spectroscopy experiments, and in an unrestrained geometry, as in the in vivo degradation process. In open pore configurations, unfolding of unrestrained SPs occurs via an unzipping mechanism, which involves force application along a weak mechanical direction. In the partially closed pore, unfolding occurs via a shearing mechanism, with force application along a strong mechanical direction. By contrast, unfolding of the restrained I27 is limited to a shearing mechanism due to application of force along the strong mechanical direction. We propose that Clp nanomachine plasticity underlies direction-dependent pulling mechanisms that enable versatile SP remodeling actions.

Keratoconus is a common corneal ectasia that leads to progressive visual impairment. Numerous studies have shown abnormal protein expression patterns in keratoconic corneas. However, the specific mechanisms causing this disease remain ambiguous. This review aims to provide an update on morphological studies of the keratoconic cornea, relate these early studies with current findings from proteomic, biochemical and cell culture studies and to postulate possible pathogenic pathways.

Purpose.Abnormal protein deposits includingβ-amyloid, found in ageing Bruch’s membrane and brain, are susceptible to degradation by matrix metalloproteinases (MMPs). In ageing Bruch’s membrane, these MMPs become less effective due to polymerisation and aggregation reactions (constituting the MMP Pathway), a situation much advanced in age-related macular degeneration (AMD). The likely presence of this MMP Pathway in brain with the potential to compromise the degradation ofβ-amyloid associated with Alzheimer’s disease (AD) has been investigated.Methods.Presence of high molecular weight MMP species (HMW1 and HMW2) together with the much larger aggregate termed LMMC was determined by standard zymographic techniques. Centrigugation and gel filtration techniques were used to separate and quantify the distribution between bound and free MMP species.Results.The MMP Pathway, initially identified in Bruch’s membrane, was also present in brain tissue. The various MMP species displayed bound-free equilibrium and in AD samples, the amount of bound HMW1 and pro-MMP9 species was significantly reduced (p<0.05). The abnormal operation of the MMP Pathway in AD served to reduce the degradation potential of the MMP system.Conclusion.The presence and abnormalities of the MMP Pathway in both brain and ocular tissues may therefore contribute to the anomalous deposits associated with AD and AMD.

Hereditary transthyretin amyloidosis is an inherited disorder that results in the gradual progressive deposit of abnormal protein called amyloid in the body’s organs and tissues. There are currently no approved drugs to treat transthyretin amyloidosis, and patients may require liver transplantation for survival. There are a few drugs in development to treat hereditary transthyretin amyloidosis either by stabilizing the abnormal protein or by decreasing production of transthyretin. Both methods are being developed to slow progression of the disease.

Background In this study, we aimed to test the clinical value of total prostate-specific antigen (T-PSA), free prostate-specific antigen (F-PSA), and T-PSA combined with tumor abnormal glycoprotein (TAP) for early diagnosis of prostate cancer. Methods The levels of serum T-PSA and F-PSA were measured in 105 malignant prostate tumors and 97 benign prostate tissues using chemiluminescence immunoassay. The concentration of TAP in the serum of patients was tested by the agglutination method. Differences in PSA levels and F-PSA/T-PSA ratio in two patient groups were analyzed by t-test. TAP concentrations were compared using Chi-square test. The sensitivity, specificity, and accuracy of PSA combined with TAP for the diagnosis of prostate cancer were analyzed. Results The serum PSA level in patients with malignant tumors were higher than that in patients with benign tumors (P

Abnormal protein aggregation is a common pathological feature of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Protein posttranslational modifications (PTMs) play a crucial regulatory role in the formation of pathologic aggregation. Among the known PTMs involved in neurodegeneration, poly(ADP-ribosylation) (PARylation) has emerged with promising therapeutic potentials of the use of poly(ADP-ribose) (PAR) polymerase (PARP) inhibitors. In this review, we describe the mounting evidence that abnormal PARP activation is involved in various neurodegenerative diseases, and discuss the underpinning mechanisms with a focus on the recent findings that PARylation affects liquid-liquid phase separation and aggregation of amyloid proteins. We hope this review will stimulate further investigation of the unknown functions of PARylation and promote the development of more effective therapeutic agents in treating neurodegeneration.

Prions are defined as proteinaceous infectious particles that do not contain nucleic acids. Neuropathological investigations of post-mortem brains and recent studies of experimental transmission have suggested that amyloid-like abnormal protein aggregates, which are the defining feature of many neurodegenerative diseases, behave like prions and propagate throughout the brain. This prion-like propagation may be the underlying mechanism of onset and progression of neurodegenerative diseases, although the precise molecular mechanisms involved remain unclear. However, in vitro and in vivo experimental models of prion-like propagation using pathogenic protein seeds are well established and are extremely valuable for the exploration and evaluation of novel drugs and therapies for neurodegenerative diseases for which there is no effective treatment. In this chapter, we introduce the experimental models of prion-like propagation of α-synuclein, which is accumulated in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, and we describe their applications for the development of new diagnostic and therapeutic modalities. We also introduce the concept of "α-syn strains," which may underlie the pathological and clinical diversity of α-synucleinopathies.