Neurodegenerative diseases are currently some of the most debilitating and incurable illness, including highly prevalent disorders, such as Alzheimer's and Parkinson's disease. Despite impressive advances in understanding the molecular basis of neurodegenerative diseases, several clinical trials have failed in identifying drugs that successfully delay or stop disease progression. New targets are likely

Alzheimer's disease (AD) is the leading cause of dementia and sixth cause of death in elderly adults. AD poses a huge economic burden on society and constitutes an unprecedented challenge for caregivers and families affected. Aging of the population is projected to drastically aggravate the situation in the near future. To date, no therapy is available to prevent or ameliorate the disease. Moreover

After Alzheimer's disease, Parkinson's disease is the most frequent neurodegenerative disorder. Although numerous treatments have been developed to control the disease symptomatology, with some successes, an efficacious therapy affecting the causes of PD is still a goal to pursue. The genetic evidence and the identification of α-synuclein as the main component of intracellular Lewy bodies, the neuropathological

The human body is home to a diverse and functionally important assemblage of symbiotic microbes that varies predictably over different spatial scales, both within and across body sites. The composition of these spatially distinct microbial consortia can be impacted by a variety of stochastic and deterministic forces, including dispersal from different source communities, and selection by regionally-specific

The existence of a bidirectional communication system termed the “gut-brain axis” linking the gastrointestinal tract with the brain has been recognized since the nineteenth century. In the last decades, however, it has become evident that the saprophytic gut microbial flora plays a key role in the modulation of this gut-brain connecting pathway, which is defined now as the “microbiota-gut-brain axis”

The microbiome is the ecological community of commensal, symbiotic, and pathogenic microorganisms that share our body space (Medical and Health Genomics, 2016, page 15–28). The human gut is the location where the maximum number of microorganisms can be found. Among the different microorganisms they can be broadly classified into two groups: the beneficial and harmful. In the human gut there is always

The idea that trillions of bacteria inhabit our gut is somewhat unnerving, yet these bacteria may have a greater influence on our behavior than previously thought. Accumulating data strongly suggest that these gut commensal organisms have a strong inter-relationship with our brain and behavior, including cognitive function, mood, and personality. In this chapter, we discuss the role of the gut microbiome

The scientific community currently defines the human microbiome as all the bacteria, viruses, fungi, archaea, and eukaryotes that occupy the human body. When considering the variable locations, composition, diversity, and abundance of our microbial symbionts, the sheer volume of microorganisms reaches hundreds of trillions. With the onset of next generation sequencing (NGS), also known as high-throughput

Here I present the scientific rationale and implementation strategies for elimination of early-onset neurodegenerative disorders (EONDD) from future generations, and for risk reduction and treatments for the more common late-onset neurodegenerative disorders (LONDD). Young adults with a family history of an EONDD should be educated on the genetics and familial burden of EONDD. They can then be genotyped

New neurons are generated in the dentate gyrus of the adult brain throughout life. They incorporate in the granular cell layer of the dentate gyrus and integrate in the hippocampal circuitry. Increasing evidence suggests that new neurons play a role in learning and memory. In turn, a large body of evidence suggests that neurogenesis is impaired in Alzheimer's disease, contributing to memory deficits

Human prion disease may present in a non-specific way and is often diagnosed at a relatively late stage of the illness. Until recently, clinical diagnosis has been supported by tests that are mostly non-specific and, sometimes, insensitive. Recent laboratory developments have led to a variety of tests that rely on a disease-specific mechanism. One test, the CSF RT-QuIC (Real-Time Quaking-Induced Conversion)

Since their original identification, prions have represented enigmatic agents that defy the classical concept of genetic inheritance. For almost four decades, the high-resolution structure of PrPSc, the infectious and misfolded counterpart of the cellular prion protein (PrPC), has remained elusive, mostly due to technical challenges posed by its high insolubility and aggregation propensity. As a result

Mammalian prion or PrPSc is a proteinaceous infectious agent that consists of a misfolded, self-replicating state of a sialoglycoprotein called the prion protein or PrPC. Sialylation of the prion protein, a terminal modification of N-linked glycans, was discovered more than 30 years ago, yet the role of sialylation in prion pathogenesis is not well understood. This chapter summarizes current knowledge

The protein-only hypothesis predicts that infectious mammalian prions are composed solely of PrPSc, a misfolded conformer of the normal prion protein, PrPC. However, to date, all wild type protein-only PrPSc preparations lack significant levels of prion infectivity. Using a systemic biochemical approach, our laboratory isolated and identified two different endogenous cofactor molecules, RNA (Deleault

Prions are a self-propagating misfolded conformation of a cellular protein. Prions are found in several eukaryotic organisms with mammalian prion diseases encompassing a wide range of disorders. The first recognized prion disease, the transmissible spongiform encephalopathies (TSEs), affect several species including humans. Alzheimer's disease, synucleinopathies, and tauopathies share a similar mechanism

Transmissible spongiform encephalopathies or prion diseases describe a number of different human disorders that differ in their clinical phenotypes, which are nonetheless united by their transmissible nature and common pathology. Clinical variation in the absence of a conventional infectious agent is believed to be encoded by different conformations of the misfolded prion protein. This misfolded protein

Prions are unique agents that challenge the molecular biology dogma by transmitting information on the protein level. They cause neurodegenerative diseases that lack of any cure or treatment called transmissible spongiform encephalopathies. The function of the normal form of the prion protein, the exact mechanism of prion propagation between species as well as at the cellular level and neuron degeneration

The transmission of prions between species is typically an inefficient process due to the species barrier, which represents incompatibility between prion seed and substrate molecules. Bank voles (Myodes glareolus) are an exception to this rule, as they are susceptible to a diverse range of prion strains from many different animal species. In particular, bank voles can be efficiently infected with most

Misfolding and aggregation of proteins play a central role in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's and Lewy Body diseases, Frontotemporal Lobar Degeneration and prion diseases. Increasing evidence supports the view that Aβ and tau, which are the two main molecular players in AD, share with the prion protein several “prion-like” features

The ordered assembly of a small number of proteins into amyloid filaments is central to age-related neurodegenerative diseases. Tau is the most commonly affected of these proteins. In sporadic diseases, assemblies of tau form in a stochastic manner in certain brain regions, from where they appear to spread in a deterministic way, giving rise to disease symptoms. Over the past decade, multiple lines

The misfolding, aggregation, and deposition of specific proteins is the key hallmark of most progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). ALS is characterized by the rapid and progressive degenerations of motor neurons in the spinal cord and motor cortex, resulting in paralysis of those who suffer from it. Pathologically

Neurodegenerative disorders are invariably associated with intra- or extra-cellular deposition of aggregates composed of misfolded insoluble proteins. These deposits composed of tau, amyloid-β or α-synuclein spread from cell to cell, in a prion-like manner. Emerging evidence suggests that the circulating soluble species of these misfolded proteins (usually referred as oligomers) could play a major

Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), atypical parkinsonisms, frontotemporal dementia (FTLD) and prion diseases are characterized by the accumulation of misfolded proteins in the central nervous system (CNS). Although the cause for the initiation of protein aggregation is not well understood, these aggregates are disease-specific. For instance

Here we describe the principles of protein surgery and its application to the molecular design for regulating the protein conformation. We initially describe the Poincare duality that defines the basis of complementarity in the time-dependent geometrical space. Next we introduce the theory of protein surgery consisting of “dissection” and “suture,” which correspond to differentiation and integration

Recent data establish multiple defects in endocytic functions as early events initiating various neurodegenerative disorders, including Alzheimer's disease (AD). The genetic landscape resulting from genome-wide association studies (GWAS) reveals changes in post-endocytic trafficking of amyloid precursor protein (APP) in neurons leading to an increase in amyloidogenic processing, deficits in amyloid

Over the last several decades, a number of mouse models have been generated for mechanistic and preclinical therapeutic research on Alzheimer's disease (AD)-like behavioral impairments and pathology. Acceptance or rejection of these models by the scientific community is playing a prominent role in how research findings are viewed and whether grants get funded and manuscripts published. The question

Alzheimer's disease (AD) is a complex disease of the brain. Despite over 100 years of basic and clinical research, significantly intensified in the last three decades, the exact cause of this neurodegeneration is still an enigma. Based on neuroanatomical, experimental, and clinical findings, a series of hypotheses on AD pathogenesis have evolved. Among them, the “amyloid cascade hypothesis” has been

The 1102-amino-acid activity-dependent neuroprotective protein (ADNP) was originally discovered by expression cloning through the immunological identification of its 8-amino-acid sequence NAPVSIPQ (NAP), constituting the smallest active neuroprotective fragment of the protein. ADNP expression is essential for brain formation and cognitive function and is dysregulated in a variety of neurodegenerative

During animal development, HOX transcription factors determine the fate of developing tissues to generate diverse organs and appendages. The power of these proteins is striking: mis-expressing a HOX protein causes homeotic transformation of one body part into another. During development, HOX proteins interpret their cellular context through protein interactions, alternative splicing, and post-translational

Being responsible for more than 90% of cellular functions, protein molecules are workhorses in all the life forms. In order to cater for such a high demand, proteins have evolved to adopt diverse structures that allow them to perform myriad of functions. Beginning with the genetically directed amino acid sequence, the classical understanding of protein function involves adoption of hierarchically complex

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder thought to be caused by predisposing high-risk genes that may be altered during the early development by environmental factors. The impact of maternal challenges during pregnancy on the prevalence of ASD has been widely studied in clinical and animal studies. Here, we review some clinical and pre-clinical evidence that links environmental

Directed stabilization of globular proteins via substitution of a minimal number of amino acid residues is one of the most complicated experimental tasks. In this work, we have successfully used algorithms for the evaluation of intrinsic disorder predisposition (such as PONDR® FIT and IsUnstruct) as tools for searching for the weakened regions in structured globular proteins. We have shown that the

G protein-coupled receptors (GPCRs) and Nuclear Receptors (NRs) are two signaling machineries that are involved in major physiological processes and, as a consequence, in a substantial number of diseases. Therefore, they actually represent two major targets for drugs with potential applications in almost all public health issues. Full exploitation of these targets for therapeutic purposes nevertheless

The double face of nickel, being both a toxic element for living organisms and a necessary metal for enzymatic reactions, forces nickel-dependent organisms to develop regulatory networks in order to tightly control the intracellular Ni(II) ion quota, avoiding the occurrence of a free Ni(II) pool and overcoming the natural scarcity of this metal ion in the environment. Among nickel-dependent enzymes

Autism spectrum disorder (ASD) is a set of pervasive neurodevelopmental disorders. The causation is multigenic in most cases, which makes it difficult to model the condition in vitro. Advances in pluripotent stem cell technology has made it possible to generate in vitro models of human brain development. Induced pluripotent stem cells (iPSCs) can be generated from somatic cells and have the ability

A substantive volume of research on autism spectrum disorder (ASD) has emerged in recent years adding to our understanding of the etiopathological process. Preclinical models in mice and rats have been highly instrumental in modeling and dissecting the contributions of a multitude of known genetic and environmental risk factors. However, the translation of preclinical data into suitable drug targets

Correlation and association analyses are one of the most widely used statistical methods in research fields, including microbiome and integrative multiomics studies. Correlation and association have two implications: dependence and co-occurrence. Microbiome data are structured as phylogenetic tree and have several unique characteristics, including high dimensionality, compositionality, sparsity with

The cellular recycling process of macroautophagy, which is the mechanism by which cellular material is delivered to lysosomes via double membraned vesicles called autophagosomes, is intimately connected to programmed cell death pathways, especially apoptosis. In this article, I discuss some underlying mechanisms and their implications for improving cancer therapy and propose that the approaches that

Autism spectrum disorder is a neurodevelopmental disorder characterized by impaired development and by abnormal function in regards to social interaction, communication and restricted, repetitive behavior. It affects approximately 1% of the worldwide population. Like other psychiatric disorders the diagnosis is based on observation of, and interview with the patient and next of kin, and diagnostic

Highly complex endophenotypes and underlying molecular mechanisms have prevented effective diagnosis and treatment of autism spectrum disorder. Despite extensive studies to identify relevant biosignatures, no biomarker and therapeutic targets are available in the current clinical practice. While our current knowledge is still largely incomplete, -omics technology and machine learning-based big data

Altered sensory processing and perception has been one of the characteristics of autism spectrum disorder (ASD). In this chapter, we review the neural underpinnings of sensory abnormalities of ASD by examining the literature on clinical, behavioral and neurobiological evidence that underlies the main patterns of sensory integration function and dysfunction. Furthermore, neural differences in anatomy

The development of new approaches for the clinical management of autism spectrum disorder (ASD) can only be realized through a better understanding of the neurobiological changes associated with ASD. One strategy for gaining deeper insight into the neurobiological mechanisms associated with ASD is to identify converging pathogenic processes associated with human idiopathic clinicopathology that are

Liquid-liquid phase separation (LLPS) brings together functionally related proteins through the intrinsic biophysics of proteins in a process that is driven by reducing free energy and maximizing entropy. The process of LLPS allows proteins to form structures, termed membrane-less organelles. These diverse, dynamic organelles are active in a wide range of processes in the nucleus, cytoplasm, mitochondria

Autophagy is a cellular housekeeping and quality control mechanism that is essential for homeostasis and survival. By virtue of this role, any perturbations to the flow of this process in cardiac or vascular cells can elicit harmful effects on the cardiovascular system, and subsequently affect whole organismal health. In this chapter, we summarize the preclinical evidence supporting the role of autophagy

Neurodevelopmental impairment remains a significant morbidity in former very low birth weight premature infants. There is increasing evidence the microbiome affects neurodevelopment but mechanistic causes are largely unknown. There are many factors which affect the developing microbiome in infants including mode of delivery, feeding, medications, and environmental exposures. The overall impact of these

Since the initial psychological report by Leo Kanner in 1943, relatively little formal biochemical/neurological research on the cause of autism, other than peripheral searches for genomic mutations, had been carried until the end of the 20th century. As a result of studies on twin sets and the conclusion that autism was largely a hereditary defect, numerous investigations have sought various genetic

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by difficulties in social communication and the presence of restricted interests and repetitive behaviors. Although behavioral interventions are numerous, there are no Federal Drug Administration approved pharmacological treatments for the core symptoms of ASD. The neuropeptide oxytocin has been studied in animals for decades

A reliable diagnosis of autism spectrum disorder (ASD) is difficult to make until after toddlerhood. Detection in an earlier age enables early intervention, which is typically more effective. Recent studies of the development of brain and behavior in infants and toddlers have provided important insights in the diagnosis of autism. This extensive review focuses on published studies of predicting the

Various genetic and environmental factors have been suggested to cause autism spectrum disorders (ASDs). A variety of animal models of ASDs have been developed and used to investigate the mechanisms underlying the pathogenesis of ASDs. These animal models have contributed to clarifying that abnormalities in neuronal morphology and neurotransmission are responsible for the onset of ASDs. In recent years

Neuroglia are a large class of neural cells of ectodermal (astroglia, oligodendroglia, and peripheral glial cells) and mesodermal (microglia) origin. Neuroglial cells provide homeostatic support, protection, and defense to the nervous tissue. Pathological potential of neuroglia has been acknowledged since their discovery. Research of the recent decade has shown the key role of all classes of glial

The posterior cingulate cortex (PCC) plays pivotal roles in cognitive, social and emotional processing, as well as early neural development that supports complex interactions among different neural networks. Alterations in its local and long-range connectivity during resting state are often implicated in neuropathology of neurodevelopmental disorders such as autism spectrum disorder (ASD). ASD is characterized

In the past decades, the fields of microbiology and immunology have largely advanced by using germ-free animals and next-generation sequencing. Many studies revealed the relationship among gut microbiota, activation of immune system, and various diseases. Especially, some gut commensals can generate their antigen-specific T cells. It is becoming clear that commensal bacteria have important roles in

Cancer treatment has been evolving in recent decades from surgery, conventional chemotherapy and radiation therapy to targeted therapies and more recently immunotherapies. Despite significant improvement in the efficacy of treatment with the discovery of novel therapies targeting particular cancer-related gene and proteins and more recently the immune system-modulating biologics, still only patients

Type 1 diabetes (T1D) is an autoimmune disease caused by complex interactions between host genetics and environmental factors, culminating in the T-cell mediated destruction of the insulin producing cells in the pancreas. The rapid increase in disease frequency over the past 50 years or more has been too rapid to attribute to genetics. Dysbiosis of the gut microbiota is currently being widely investigated

Although there is associative evidence linking fecal microbiome profile to health and disease, many studies have not considered the confounding effects of dietary intake. Consuming food provides fermentable substrate which sustains the microbial ecosystem that resides with most abundance in the colon. Western, Mediterranean and vegetarian dietary patterns have a role in modulating the gut microbiota

Many components of the gastric non-Helicobacter pylori microbiota have been identified recently thanks to advances in DNA sequencing techniques. Several lines of evidence support the hypothesis that the gastric microbiome is essential for gastric disorders such as gastric cancer. Microbial interactions impact the pathophysiology of various gastric disorders. This chapter provides an overview of recent

Motor neuron diseases (MNDs) are a wide group of neurodegenerative disorders characterized by the degeneration of a specific neuronal type located in the central nervous system, the motor neuron (MN). There are two main types of MNs, spinal and cortical MNs and depending on the type of MND, one or both types are affected. Cortical MNs innervate spinal MNs and these control a variety of cellular targets

The influence of the microbiota on viral infection susceptibility and disease outcome is undisputable although varies among viruses. The purpose of understanding the interactions between microbiota, virus, and host is to identify practical, effective, and safe approaches that target microbiota for the prevention and treatment of viral diseases in humans and animals, as currently there are few effective

Gut bacteria are predominant microorganisms in the gut microbiota and have been recognized to mediate a variety of biotransformations of xenobiotic compounds in the gut. This review is focused on one of the gut bacterial xenobiotic metabolisms, reduction. Xenobiotics undergo different types of reductive metabolisms depending on chemically distinct groups: azo (-NN-), nitro (-NO2), alkene (-CC-), ketone

The gut microbiota (GM) composition varies among individuals and is influenced by intrinsic (genetics, age) and extrinsic (environment, diet, lifestyle) factors. An imbalance or dysbiosis is directly associated with the development of several illnesses, due to the potential increase in intestinal permeability leading to a systemic inflammation triggered by higher levels of circulating lipopolysaccharides