Huntington's Diseases Research Articles

Resveratrol: A Focus on Several Neurodegenerative Diseases.

Molecules of the plant world are proving their effectiveness in countering, slowing down, and regressing many diseases. The resveratrol for its intrinsic properties related to its stilbene structure has been proven to be a universal panacea, especially for a wide range of neurodegenerative diseases. This paper evaluates (in vivo and in vitro) the various molecular targets of this peculiar polyphenol and its ability to effectively counter several neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases and amyotrophic lateral sclerosis. What emerges is that, in the deep heterogeneity of the pathologies evaluated, resveratrol through a convergence on the protein targets is able to give therapeutic responses in neuronal cells deeply diversified not only in morphological structure but especially in their function performed in the anatomical district to which they belong.

Striatopallidal NMDA-receptors control locomotor and conditioning behaviours.

Event Abstract Back to Event Striatopallidal NMDA-receptors control locomotor and conditioning behaviours. Laurie Lambot1*, Elena Chaves Rodriguez1, Yuqing Li2, Serge N. Schiffmann1, Alban De Kerchove D’Exaerde1 and David Gall1 1 Université Libre de Bruxelles, Faculté de Médecine, Belgium 2 University of Florida, College of Medicine, Department of Neurology, United States The basal ganglia (BG) are composed of several interconnected nuclei that have a critical role in goal-directed action selection, motor control, and habits. The striatum, the major input site of the BG, is predominantly composed of medium spiny neurons (MSN), which give rise to two projection circuits originating from two distinct populations of MSN: the striatonigral MSN (dMSN) give rise to the direct pathway and the striatopallidal MSN (iMSN) to the indirect pathway. Balanced activity between both pathways is crucial for harmonious functions of the BG. Imbalance of those two neuronal subpopulations is implicated in major neuropsychiatric disorders such as Parkinson and Huntington diseases as well as drug addiction. Despite the increasing knowledge concerning the key role of the striatal glutamate NMDA receptor (NMDA-R) for the BG physiology, it is still challenging to understand the specific functions of striatopallidal neuron NMDA-R. In this study, by a conditional deletion of the essential GluN1 subunit of NMDA-R specificaly in striatopallidal neurons (cKO), the functions of the NMDA-R in the indirect pathway were adressed. At the cellular level, the deletion of GluN1 in iMSN leads to the reduced number and strength of the excitatory corticostriatopalidal synapses and the intrinsic electro-responsiveness of the iMSN was higher, reflecting an homeostatic adaptation partially compensating the reduced synaptic inputs. The behavioral consequence of the NMDA-R absence in iMSN is an aberrant action selection in goal directed behaviour, without alteration of motor learning but changing of motor strategy, as well as alteration in habituation and amphetamine locomotor sensitization. Taken together, these data indicate that the loss of NMDA-R in the striatopallidal neurons disrupts operant and habituation behaviours. Acknowledgements L.L. was supported by a FRIA (Fonds pour la formation à la Recherche dans l'Industrie et dans l'Agriculture) PhD fellowship from the Fund for Scientific Research-Fonds de la Recherche Scientifique (FRS-FNRS) (Belgium) and Van Buuren grant from the fonds David et Alice Van Buuren. This study was supported by the Fondation Médicale Reine Elisabeth (Belgium). We would like to acknowledge Dr Frédéric Bollet-Quivogne of the Light Microscopy Facility (LiMiF). Keywords: NMDA receptor, Neuronal morphology, Striatum, goal-directed behavior, Synaptic Transmission Conference: 11th National Congress of the Belgian Society for Neuroscience, Mons, Belgium, 22 May - 22 May, 2015. Presentation Type: Oral or Poster presentation Topic: Neuroscience Citation: Lambot L, Chaves Rodriguez E, Li Y, Schiffmann SN, De Kerchove D’Exaerde A and Gall D (2015). Striatopallidal NMDA-receptors control locomotor and conditioning behaviours.. Front. Neurosci. Conference Abstract: 11th National Congress of the Belgian Society for Neuroscience. doi: 10.3389/conf.fnins.2015.89.00074 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Apr 2015; Published Online: 05 May 2015. * Correspondence: Miss. Laurie Lambot, Université Libre de Bruxelles, Faculté de Médecine, Bruxelles, 1070, Belgium, laurie.s.lambot@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Laurie Lambot Elena Chaves Rodriguez Yuqing Li Serge N Schiffmann Alban De Kerchove D’Exaerde David Gall Google Laurie Lambot Elena Chaves Rodriguez Yuqing Li Serge N Schiffmann Alban De Kerchove D’Exaerde David Gall Google Scholar Laurie Lambot Elena Chaves Rodriguez Yuqing Li Serge N Schiffmann Alban De Kerchove D’Exaerde David Gall PubMed Laurie Lambot Elena Chaves Rodriguez Yuqing Li Serge N Schiffmann Alban De Kerchove D’Exaerde David Gall Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Functional role of PDGFRb, a striatopallidal specific gene, in motor and motivational behavior

Event Abstract Back to Event Functional role of PDGFRb, a striatopallidal specific gene, in motor and motivational behavior Deniz Karadurmus1*, Sabrina L. Ena1, Laurie Lambot1, Alban De Kerchove D'Exaerde1 and Serge N. Schiffmann1 1 Université Libre de Bruxelles, ULB Neuroscience Institute, Belgium Basal ganglia are a set of interconnected nuclei involved in motor control and motivation. The striatum is the main input of basal ganglia and is mainly composed of medium spiny neurons, subdivided into striatopallidal (STP) and striatonigral (STN) neurons. STP and STN neurons give rise respectively to the indirect and the direct pathways of basal ganglia, with opposite effects at both motor and motivational levels. Cellular mechanisms involving these pathways in disorders such as Huntington's and Parkinson's diseases and addiction, are still poorly understood. Our laboratory has previously identified gene expression profiles of STN and STP neurons using microarray (Ena, 2013). Our project consists in the study of STP or STN specific genes function in locomotor control and addiction behavior. To this end, specific repression of genes of interest in STP or STN pathway is generated using floxed mice or shRNA interference mediated by lentivirus. Phenotypic analysis is then achieved through behavioral tests to assess the effect of gene deletion. Moreover, different experimental strategies based on molecular biology and electrophysiology are used to determine molecular mechanisms responsible for observed phenotypes. We first focused on PDGFRb because of its enrichment in STP neurons and its potential function in striatal neurons according to the literature. STP specific expression of PDGFRb has been validated, and the activation pathway of PDGFRb in STP neurons has been investigated in primary striatal cultures. We are now generating mouse model repressing PDGFRb in striatal neurons to study PDGFRb deletion effects in vivo. References Ena, S. L., De Backer, J. F., Schiffmann, S. N., de Kerchove d'Exaerde, A. (2013). FACS array profiling identifies Ecto-5' nucleotidase as a striatopallidal neuron-specific gene involved in striatal-dependent learning. J Neurosci 33, 8794-809, DOI:10.1523/JNEUROSCI.2989-12.2013 Keywords: Striatum, PDGFRB, striatopallidal pathway, striatonigral pathway, cell-type-specific gene Conference: 11th National Congress of the Belgian Society for Neuroscience, Mons, Belgium, 22 May - 22 May, 2015. Presentation Type: Poster presentation Topic: Neuroscience Citation: Karadurmus D, Ena SL, Lambot L, De Kerchove D'Exaerde A and Schiffmann SN (2015). Functional role of PDGFRb, a striatopallidal specific gene, in motor and motivational behavior. Front. Neurosci. Conference Abstract: 11th National Congress of the Belgian Society for Neuroscience. doi: 10.3389/conf.fnins.2015.89.00045 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 29 Apr 2015; Published Online: 05 May 2015. * Correspondence: Ms. Deniz Karadurmus, Université Libre de Bruxelles, ULB Neuroscience Institute, Bruxelles, 1070, Belgium, denizkaradurmus@hotmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Deniz Karadurmus Sabrina L Ena Laurie Lambot Alban De Kerchove D'Exaerde Serge N Schiffmann Google Deniz Karadurmus Sabrina L Ena Laurie Lambot Alban De Kerchove D'Exaerde Serge N Schiffmann Google Scholar Deniz Karadurmus Sabrina L Ena Laurie Lambot Alban De Kerchove D'Exaerde Serge N Schiffmann PubMed Deniz Karadurmus Sabrina L Ena Laurie Lambot Alban De Kerchove D'Exaerde Serge N Schiffmann Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Neuroprotection induced by NMDA preconditioning as a strategy to understand brain tolerance mechanism.

Excitotoxicity refers to toxicity caused by abnormal concentrations of glutamate in the synaptic cleft that may lead to neuronal death. Since its description, the phenomenon of glutamatergic excitotoxicity has been implicated in the physiopathology of a wide range of neurological and psychiatric disorders, from acute brain damage such as traumatic brain injury, ischemia as well as chronic conditions like epilepsy, depression and neurodegenerative pathologies such as Huntington's, Parkinson's and Alzheimer's diseases. Excessive stimulation of glutamatergic receptors, mainly N-methyl-D-aspartate (NMDA) receptors (NMDAR), can have numerous adverse effects on the cell viability, including increased nitric oxide release (NO), activation of proteases, increased production of reactive oxygen (ROS) and nitrogen (RNS) species and massive influx of calcium ions (Ca2+), resulting in cell death. Thus, the use of strategies that modulate the excitotoxic cell damage represents a perspective for the treatment of diseases such as Parkinson's and Alzheimer's diseases, ischemia, traumatic brain injury (TBI) and seizures.

Glypican 4 down-regulation in pluripotent stem cells as a potential strategy to improve differentiation and to impair tumorigenicity of cell transplants.

Recent advances in stem cell technologies have opened new avenues for the treatment of a number of diseases still lacking effective therapeutic options. Cell transplantation has emerged as among the most promising clinical intervention for disorders such as injuries, diabetes, liver diseases, neurodegeneration and heart failure (Lee et al., 2013; Forbes and Rosenthal, 2014; Tabar and Studer, 2014). To date much attention is given to the potential application of human pluripotent stem cells (hPSCs) including both embryonic (hESCs) and induced pluripotent stem cells (hiPSCs) for regenerative medicine (Yamanaka, 2012; Lee et al., 2013; Tabar and Studer, 2014). Owing to their remarkable ability to self-renewal indefinitely and to differentiate into all mature cell types hPSCs appear of great advantage to generate an unlimited number of disease-relevant cells. The benefits/pitfalls associated with the use of hPSCs and their derivatives in cell-based transplantation therapies are currently being evaluated in animal models recapitulating human conditions (Hulot et al., 2014; Isacson, 2015). In vivo studies have begun to provide proof-of-concept for the efficacy of hPSC-based transplantation therapies to treat pathologies such as Parkinson's, Huntington's and retinal diseases in which symptoms are caused by the selective loss of specific cell types (Tabar and Studer, 2014; Isacson, 2015). Interestingly, cell transplantation therapies utilizing hPSC-derived retinal pigment epithelium cells have reached clinical trials for the treatment of macular degeneration.

Fractalkine: multiple strategies to counteract glutamate receptors activation leading to neuroprotection.

Fractalkine: multiple strategies to counteract glutamate receptors activation leading to neuroprotection.

Amyloid misfolding, aggregation, and the early onset of protein deposition diseases: insights from AFM experiments and computational analyses.

The development of Alzheimer’s disease is believed to be caused by the assembly of amyloid β proteins into aggregates and the formation of extracellular senile plaques. Similar models suggest that structural misfolding and aggregation of proteins are associated with the early onset of diseases such as Parkinson’s, Huntington’s, and other protein deposition diseases. Initially, the aggregates were structurally characterized by traditional techniques such as x-ray crystallography, NMR, electron microscopy, and AFM. However, data regarding the structures formed during the early stages of the aggregation process were unknown. Experimental models of protein deposition diseases have demonstrated that the small oligomeric species have significant neurotoxicity. This highlights the urgent need to discover the properties of these species, to enable the development of efficient diagnostic and therapeutic strategies. The oligomers exist transiently, making it impossible to use traditional structural techniques to study their characteristics. The recent implementation of single-molecule imaging and probing techniques that are capable of probing transient states have enabled the properties of these oligomers to be characterized. Additionally, powerful computational techniques capable of structurally analyzing oligomers at the atomic level advanced our understanding of the amyloid aggregation problem. This review outlines the progress in AFM experimental studies and computational analyses with a primary focus on understanding the very first stage of the aggregation process. Experimental approaches can aid in the development of novel sensitive diagnostic and preventive strategies for protein deposition diseases, and several examples of these approaches will be discussed.

Perspectives on the Emerging Applications of Multifaceted Biomedical Polymeric Nanomaterials

Biodegradable and biocompatible polymeric nanomaterials, serving as biomedical devices have garnered significant attention as a promising solution to therapeutic management of many chronic diseases. Despite their potentials, majority of the synthetic nanomaterials used in biomedical applications lack crucial properties, for example, ligand binding sites, responsiveness, and switchability to efficiently deliver intended drugs to the target site. Advancements in manipulating nanoscale geometry have incurred the incorporation of triggered release mechanism within the nanomaterials design. This expanded their potential applications beyond nanocarriers to theranostics exhibiting both tandem drug delivery and diagnostic capabilities. Additionally, it highlights possibilities to design nanomaterials that could translate chemical response(s) to photometric display, thus making affordable biosensors and actuators readily available for biomedical exploitation. It is anticipated that, in the near future, these implementations could be made to access some of the most difficult therapy locations, for example, blood brain barrier to provide efficient management of Alzheimer, Huntington, and other neurodegenerative diseases. This review aims to serve as a reference platform by providing the readers with the overview of the recent advancements and cutting‐edge techniques employed in the production and instrumentation of such nanomaterials.

Mechanisms of amyloid fibril formation.

Amyloid and amyloid-like aggregates are elongated unbranched fibrils consisting of β-structures of separate monomers positioned perpendicular to the fibril axis and stacked strictly above each other. In their physicochemical properties, amyloid fibrils are reminiscent of synthetic polymers rather than usual proteins because they are stable to the action of denaturing agents and proteases. Their mechanical stability can be compared to a spider's web, that in spite of its ability to stretch, is stronger than steel. It is not surprising that a large number of diseases are accompanied with amyloid fibril depositing in different organs. Pathologies provoked by depositing of incorrectly folded proteins include Alzheimer's, Parkinson's, and Huntington's diseases. In addition, this group of diseases involves mucoviscidosis, some types of diabetes, and hereditary cataracts. Each type of amyloidosis is characterized by aggregation of a certain type of protein that is soluble in general, and thus leads to specific distortions of functions of the corresponding organs. Therefore, it is important to understand the process of transformation of "native" proteins to amyloid fibrils to clarify how these molecules acquire such strength and what key elements of this process determine the pathway of erroneous protein folding. This review presents our analysis of complied information on the mechanisms of formation and biochemical properties of amyloid fibrils.

Investigating dynamic structural and mechanical changes of neuroblastoma cells associated with glutamate-mediated neurodegeneration.

Glutamate-mediated neurodegeneration resulting from excessive activation of glutamate receptors is recognized as one of the major causes of various neurological disorders such as Alzheimer's and Huntington's diseases. However, the underlying mechanisms in the neurodegenerative process remain unidentified. Here, we investigate the real-time dynamic structural and mechanical changes associated with the neurodegeneration induced by the activation of N-methyl-D-aspartate (NMDA) receptors (a subtype of glutamate receptors) at the nanoscale. Atomic force microscopy (AFM) is employed to measure the three-dimensional (3-D) topography and mechanical properties of live SH-SY5Y cells under stimulus of NMDA receptors. A significant increase in surface roughness and stiffness of the cell is observed after NMDA treatment, which indicates the time-dependent neuronal cell behavior under NMDA-mediated neurodegeneration. The present AFM based study further advance our understanding of the neurodegenerative process to elucidate the pathways and mechanisms that govern NMDA induced neurodegeneration, so as to facilitate the development of novel therapeutic strategies for neurodegenerative diseases.

Clinical workout for the early detection of cognitive decline and dementia.

Aging is the major risk factor for the development of human neurodegenerative maladies such as Alzheimer's, Huntington's and Parkinson's diseases (PDs) and prion disorders, all of which stem from toxic protein aggregation. All of these diseases are correlated with cognitive decline. Cognitive Decline is a dynamic state from normal cognition of aging to dementia. According to the original criteria for Alzheimer's Disease (AD) (1984), a clinical diagnosis was possible only when someone was already demented. The prevalence rates of Cognitive Decline (mild cognitive impairment plus dementia) are very high now and will be higher in future because of the increasing survival time of people. Many neurological and psychiatric diseases are correlated with cognitive decline. Diagnosis of cognitive decline is mostly clinical (clinical criteria), but there are multiple biomarkers that could help us mostly in research programs such as short or long, paper and pencil or computerized neuropsychological batteries for cognition, activities of daily living and behavior, electroencephalograph, event-related potentials, and imaging-structural magnetic resonance imaging (MRI) and functional (fMRI, Pittsburgh bound positron emission tomography, FDG-PET, single photon emission computerized tomography and imaging of tau pathology)-cerebrospinal fluid proteins (Abeta, tau and phospho-tau in AD and α-synuclein (αSyn) for PD). Blood biomarkers need more studies to confirm their usefulness. Genetic markers are also studied but until now are not used in clinical praxis. Finally, in everyday clinical praxis and in research workout for early detection of cognitive decline, the combination of biomarkers is useful.

Distribution of the creatine transporter throughout the human brain reveals a spectrum of creatine transporter immunoreactivity.

Creatine is a molecule that supports energy metabolism in cells. It is carried across the plasma membrane by the creatine transporter. There has been recent interest in creatine for its neuroprotective effects in neurodegenerative diseases and its potential as a therapeutic agent. This study represents the first systematic investigation of the distribution of the creatine transporter in the human brain. We have used immunohistochemical techniques to map out its location and the intensity of staining. The transporter was found to be strongly expressed, especially in the large projection neurons of the brain and spinal cord. These include the pyramidal neurons in the cerebral cortex, Purkinje cells in the cerebellar cortex, and motor neurons of the somatic motor and visceromotor cranial nerve nuclei and the ventral horn of the spinal cord. Many other neurons in the brain also had some degree of creatine transporter immunoreactivity. By contrast, the medium spiny neurons of the striatum and the catecholaminergic neurons of the substantia nigra and locus coeruleus, which are implicated in neurodegenerative diseases, showed a very low to almost absent level of immunoreactivity for the transporter. We propose that the distribution may reflect the energy consumption by different cell types and that the extent of creatine transporter expression is proportional to the cell's energy requirements. Furthermore, the distribution indicates that supplemented creatine would be widely taken up by brain cells, although possibly less by those cells that degenerate in Huntington's and Parkinson's diseases.

Attentional Set-Shifting in Rodents: A Review of Behavioural Methods and Pharmacological Results

Attentional set-shifting tasks have been used as a measure of human fronto-executive function for over 60 years. The major contribution these tasks have made has been the quantification of cognitive deficits associated with human pathologies such as schizophrenia, attention deficit/hyperactivity disorder and dementias related to Parkinson's, Huntington's and Alzheimer's diseases. Thirteen years ago an intradimensional/extradimensional attentional set-shifting task was developed for rats. Since then, there have been over 70 publications detailing the effects of various manipulations on task performance in rats, and 17 publications describing adaptations of the task for mice. Much of this literature has focused on animal models of neuropathology and cognitive deficits associated with schizophrenia and other human conditions. Altogether, these results have elucidated the roles of multiple neurotransmitters in the manifestation of cognitive deficits, and their subsequent amelioration, including dopamine, serotonin, acetylcholine and noradrenaline. However, the fundamental promise of the attentional set-shifting task, to measure cognitive flexibility in humans and rodents in a formally analogous way, has often been under investigated and over simplified. This review explores the research that led to the development of the rat attentional set-shifting task, and how subsequent use of the task has expanded our understanding of the psychological and neurological underpinnings of discrimination and reversal learning, as well as the formation, maintenance and shifting of attentional set.

The chaperone Grp78 in protein folding disorders of the nervous system.

Chaperones are essential for the proper folding of proteins, and their dysfunction or depletion may be a key factor in protein folding disorders in the central nervous system. In normal conditions the cell regulates the proper folding of proteins by endoplasmic reticulum chaperones, called heat shock proteins, the cellular machinery that correctly folds newly synthesized and partially folded proteins or initiates degradation of misfolded proteins. Maintaining protein homeostasis within the cell is vital for the cells to function and survive. However, under conditions of cellular stress, proteastatic mechanisms must be activated to recycle, refold, or initiate degradation of misfolded or unfolded proteins. In this commentary, we will discuss the importance of chaperones, more specifically the 78kd glucose regulated protein Grp78 (also known as BiP and HSP5a), in Parkinson's, Alzheimer's, Huntington's, and prion diseases, and the role that metals may play in exacerbating neurodegenerative diseases.

Non-protein components of Arthrospira (Spirulina) platensis protect PC12 cells against iron-evoked neurotoxic injury

The abnormal accumulation of iron in the brain has been suggested to be toxic to neuronal cells and proposed as a possible cause of neurodegenerative disorders. Particularly, studies on the pathogenesis of neurodegenerative diseases have suggested that the excessive accumulation of iron in the specific brain regions may be responsible for neurodegenerative changes associated with the pathogenesis of Alzheimer's, Parkinson's, and Huntington's diseases. As a part of studies searching for natural substances protecting neuronal cells against the iron-evoked toxic injury, an aqueous extract containing the non-protein components of the cyanobacterium Arthrospira (Spirulina) platensis, designated “the protein-deprived extract”, was prepared, and its effect on the iron-evoked damage to PC12 cells was examined in an in vitro model experiment. The protein-deprived extract caused a protective effect against the iron-evoked damage to PC12 cells as a consequence of preventing the free radical-evoked DNA degradation. Further studies showed that the extract has antioxidant and free radical-scavenging activities, which might be based on polyphenolic compounds in the extract. Thus, polyphenolic compounds contained in A. platensis are suggested to be potentially active substances responsible for the protective effect of Arthrospira extract against the iron-evoked neurotoxicity and possibly for the protection of neurodegenerative disorders induced by excessive iron accumulation in the brain.

Hot spot of structural ambivalence in prion protein revealed by secondary structure principal component analysis.

The conformational conversion of proteins into an aggregation-prone form is a common feature of various neurodegenerative disorders including Alzheimer's, Huntington's, Parkinson's, and prion diseases. In the early stage of prion diseases, secondary structure conversion in prion protein (PrP) causing β-sheet expansion facilitates the formation of a pathogenic isoform with a high content of β-sheets and strong aggregation tendency to form amyloid fibrils. Herein, we propose a straightforward method to extract essential information regarding the secondary structure conversion of proteins from molecular simulations, named secondary structure principal component analysis (SSPCA). The definite existence of a PrP isoform with an increased β-sheet structure was confirmed in a free-energy landscape constructed by mapping protein structural data into a reduced space according to the principal components determined by the SSPCA. We suggest a "spot" of structural ambivalence in PrP-the C-terminal part of helix 2-that lacks a strong intrinsic secondary structure, thus promoting a partial α-helix-to-β-sheet conversion. This result is important to understand how the pathogenic conformational conversion of PrP is initiated in prion diseases. The SSPCA has great potential to solve various challenges in studying highly flexible molecular systems, such as intrinsically disordered proteins, structurally ambivalent peptides, and chameleon sequences.

Cholesterol Homeostasis Failure in the Brain: Implications for Synaptic Dysfunction and Cognitive Decline

Cholesterol is one of the most important molecules in cell physiology because of its involvement in several biological processes: for instance, it determines both physical and biochemical properties of cell membranes and proteins. Disruption to cholesterol homeostasis leads to coronary heart disease, atherosclerosis and metabolic syndrome. Strong evidence suggests that cholesterol also has a crucial role in the brain as various neurological and neurodegenerative disorders, including Alzheimer's, Huntington's and Parkinson diseases are associated with disruptions to cholesterol homeostasis. Here, we summarize the current knowledge about the role cholesterol plays at synaptic junctions and the pathological consequences caused by disruptions in the homeostatic maintenance of this compound.

Differential hippocampal gene expression and pathway analysis in an etiology-based mouse model of major depressive disorder.

We have recently reported the creation and initial characterization of an etiology-based recombinant mouse model of a severe and inherited form of Major Depressive Disorder (MDD). This was achieved by replacing the corresponding mouse DNA sequence with a 6-base DNA sequence from the human CREB1 promoter that is associated with MDD in individuals from families with recurrent, early-onset MDD (RE-MDD). In the current study, we explored the effect of the pathogenic Creb1 allele on gene expression in the mouse hippocampus, a brain region that is altered in structure and function in MDD. Mouse whole-genome profiling was performed using the Illumina MouseWG-6 v2.0 Expression BeadChip microarray. Univariate analysis identified 269 differentially-expressed genes in the hippocampus of the mutant mouse. Pathway analyses highlighted 11 KEGG pathways: the phosphatidylinositol signaling system, which has been widely implicated in MDD, Bipolar Disorder, and the action of mood stabilizers; gap junction and long-term potentiation, which mediate cognition and memory functions often impaired in MDD; cardiac muscle contraction, insulin signaling pathway, and three neurodegenerative brain disorders (Alzheimer's, Parkinson's, and Huntington's Diseases) that are associated with MDD; ribosome and proteasome pathways affecting protein synthesis/degradation; and the oxidative phosphorylation pathway that is key to energy production. These findings illustrate the merit of this congenic C57BL/6 recombinant mouse as a model of RE-MDD, and demonstrate its potential for highlighting molecular and cellular pathways that contribute to the biology of MDD. The results also inform our understanding of the mechanisms that underlie the comorbidity of MDD with other disorders.

Does neurology need a faster FDA?

Does neurology need a faster FDA?

Details Unfold: The Endoplasmic Reticulum Stress Response in Intestinal Inflammation and Cancer

Details Unfold: The Endoplasmic Reticulum Stress Response in Intestinal Inflammation and Cancer