Showing papers in "Journal of Molecular Neuroscience in 2011"
TL;DR: It should be considered, according to the dying back hypothesis, to focus on motor neurons terminals in order to delay or prevent the progressive degradation of motor neurons in ALS.
Abstract: Amyotrophic lateral sclerosis (ALS) is a lethal disease, characterized by progressive death of motor neurons with unknown etiology. Evidence from animal models indicates that neuronal dysfunction precedes the clinical phase of the disease. However, in parallel extensive nerve sprouting and synaptic remodeling as part of a compensatory reinnervation processes and possibly also of motor neurons pathology was demonstrated. Therefore, the weakness in muscle groups will not be clinically apparent until a large proportion of motor units are lost. This motor unit loss and associated muscle function which precedes the death of motor neurons may resemble the "die-back" phenomena. Studies indicated that in the early stages the nerve terminals and motor neuron junctions are partially degraded while the cell bodies in the spinal cord are mostly intact. Treatments to rescue motor neurons according to "dying-forward" model of motor neuron pathology in ALS have shown only limited success in SOD1(G93A) transgenic mice as well as in humans. If cell body degeneration is late compared with axonal degeneration, early intervention could potentially prevent loss of motor neurons. Therefore, it should be considered, according to the dying back hypothesis, to focus on motor neurons terminals in order to delay or prevent the progressive degradation.
312 citations
TL;DR: The timing of TJ associated proteins claudin-5, occludin, and ZO-1 in light of BBB permeability associated with cerebral ischemia reperfusion is demonstrated and suggests PKCδ pathway may participate in TJ barrier open and BBB leakage during reperfusions injury in a time-dependent manner.
Abstract: Blood–brain barrier (BBB) leakage plays a key role in cerebral ischemia–reperfusion injury. It is quite necessary to further explore the characteristic and mechanism of BBB leakage during stroke. We induced a focal cerebral ischemia model by transient middle cerebral artery occlusion in male rats for defining the time course of BBB permeability within 120 h following reperfusion and evaluate the specific role of tight junction (TJ) associated proteins claudin-5, occludin, and ZO-1 as well as protein kinase C delta (PKCδ) pathway in BBB leakage induced by reperfusion injury. We verified a bimodal increase in the permeability of the BBB following focal ischemia by Evans blue assay. Two peaks of BBB permeability appeared at 3 h and 72 h of reperfusion after 2 h focal ischemia, respectively. The leak at the endothelial cell was represented at the level of transmission electron microscopy. TTC staining results showed increased infarct size with time after cerebral ischemia reperfusion. The mRNA and protein expression levels of these three TJ associated proteins were significantly decreased compared with the sham-operated group within 120 h of reperfusion, corresponding to the time-dependent change of the biphasic pattern in BBB leakage. The redistribution of claudin-5, occludin, and ZO-1 in ischemia brain microvascular endothelial cells was observed at the same time points. In addition, Western blot assay revealed PKCδ level was also significantly increased in a similar biphasic pattern to above results within 120 h after cerebral ischemia–reperfusion. This study demonstrates the timing of TJ associated proteins claudin-5, occludin, and ZO-1 in light of BBB permeability associated with cerebral ischemia reperfusion, and suggests PKCδ pathway may participate in TJ barrier open and BBB leakage during reperfusion injury in a time-dependent manner.
309 citations
TL;DR: The anatomical distribution of tau pathology determines the clinical presentation of PSP and CBD, as well as PiD, and the basis for this selective cortical vulnerability in FTLD-tau is unknown.
Abstract: A clinically and pathologically heterogeneous type of frontotemporal lobar degeneration has abnormal tau pathology in neurons and glia (FTLD-tau). Familial FTLD-tau is usually due to mutations in the tau gene (MAPT). Even FTLD-tau determined by MAPT mutations has clinical and pathologic heterogeneity. Tauopathies are subclassified according to the predominant species of tau that accumulates, with respect to alternative splicing of MAPT, with tau proteins containing three (3R) or four repeats (4R) of ~32 amino acids in the microtubule binding domain. In Pick's disease (PiD), 3R tau predominates, whereas 4R tau is characteristic of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Depending upon the specific mutation in MAPT, familial FTLD-tau can have 3R, 4R or a combination of 3R and 4R tau. PiD is the least common FTLD-tau characterized by neuronal Pick bodies in a stereotypic neuroanatomical distribution. PSP and CBD are more common than PiD and have extensive clinical and pathologic overlap, with no distinctive clinical syndrome or biomarker that permits their differentiation. Diagnosis rests upon postmortem examination of the brain and demonstration of globose tangles, oligodendroglial coiled bodies and tufted astrocytes in PSP or threads, pretangles and astrocytic plaques in CBD. The anatomical distribution of tau pathology determines the clinical presentation of PSP and CBD, as well as PiD. The basis for this selective cortical vulnerability in FTLD-tau is unknown.
281 citations
TL;DR: It is estimated that there are approximately 20,000 to 30,000 cases of the cognitive syndromes of FTLD in the USA and the main threat to the accuracy of the estimates is the difficulty in diagnosing the clinical Syndromes that comprise the FTLD group of disorders.
Abstract: There are many challenges for determining the prevalence and incidence of frontotemporal lobar degenerations (FTLD). Consequently, the number of cases of behavioral variant frontotemporal dementia (bvFTD) or primary progressive aphasia (PPA) in the USA is unknown. Our objective was to derive a consensus estimate of bvFTD and PPA prevalence and thereby to estimate the total number of these syndromes in the USA. We identified five prevalence and three incidence studies of FTLD based on passive surveillance and seven studies of survival in FTLD. Data from these studies were used to estimate the number of cases of PPA or bvFTD in the USA. Because prevalence and incidence estimates outside of the 45–64-year age range were either not available or widely divergent, we used data from clinical and pathological series to estimate the proportion of FTLD cases aged 64 years. The prevalence estimates in the age categories of 45–64 years old have ranged from 15 to 22 per 100,000 person-years in studies where both bvFTD and PPA were identified. The incidence estimates for the same age group ranged from 2.7 to 4.1 per 100,000 person-years. Using a survival rate of 6 to 9 years from onset and rates from the incidence studies, a calculated prevalence estimate (prevalence = incidence × duration) was similar to the previously reported prevalence rates. We estimated that 10% of cases were less than age 45 years and 30% were 65 years and older. We estimate that there are approximately 20,000 to 30,000 cases of the cognitive syndromes of FTLD in the USA. The main threat to the accuracy of the estimates is the difficulty in diagnosing the clinical syndromes that comprise the FTLD group of disorders.
177 citations
TL;DR: An overview on implications and therapeutic strategies of JNK in neurodegenerative disorders is provided and the JNK pathway is considered to be a key regulator of various inflammatory pathways which are activated during normal aging and Alzheimer's disease therapy.
Abstract: The c-Jun N-terminal kinase (JNKs), also known as stress-activated protein kinase (SAPK), is one such family of multifunctional-signaling molecules, activated in response to wide range of cellular stresses as well as in response to inflammatory mediators. JNKs regulate various processes such as brain development, repair, and memory formation; but on the other hand, JNKs are potent effectors of neuroinflammation and neuronal death. A large body of evidence indicates that JNK activity is critical for normal immune and inflammatory response. Indeed, aberrant activation of JNK has been implicated in the pathogenesis of Alzheimer’s disease. Moreover, the JNK pathway is considered to be a key regulator of various inflammatory pathways which are activated during normal aging and Alzheimer’s disease therapy as well as key regulator of pro-inflammatory cytokines biosynthesis at the transcriptional and translational levels, which makes different components of these pathway potential targets for the treatment of autoimmune and inflammatory diseases. Pharmacological inhibition of JNK has been demonstrated to attenuate microglial activation and the release of neurotoxic chemicals including pro-inflammatory cytokines. In this review, we provide an overview on implications and therapeutic strategies of JNK in neurodegenerative disorders.
143 citations
TL;DR: The pathogenesis and clinical phenotype of IBMPFD caused by VCP mutations are explored and Cellular and animal models indicate pathogenetic disturbances in IB MPFD tissues including altered protein degradation, autophagy pathway alterations, apoptosis, and mitochondrial dysfunction.
Abstract: Inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) is a progressive, fatal genetic disorder with variable penetrance, predominantly affecting three main tissue types: muscle (IBM), bone (PDB), and brain (FTD). IBMPFD is caused by mutations in the ubiquitously expressed valosin-containing protein (VCP) gene, a member of the AAA-ATPase superfamily. The majority of individuals who develop IBM have progressive proximal muscle weakness. Muscle biopsies reveal rimmed vacuoles and inclusions that are ubiquitin- and TAR DNA binding protein-43 (TDP-43)-positive using immunohistochemistry. PDB, seen in half the individuals, is caused by overactive osteoclasts and is associated clinically with pain, elevated serum alkaline phosphatase, and X-ray findings of coarse trabeculation and sclerotic lesions. FTD diagnosed at a mean age of 55 years in a third of individuals is characterized clinically by comprehension deficits, dysnomia, dyscalculia, and social unawareness. Ubiquitin- and TDP-43-positive neuronal inclusions are also found in the brain. Genotype–phenotype correlations are difficult with marked intra-familial and inter-familial variations being seen. Varied phenotypes within families include frontotemporal dementia, amyotrophic lateral sclerosis, Parkinsonism, myotonia, cataracts, and anal incompetence, among others. Cellular and animal models indicate pathogenetic disturbances in IBMPFD tissues including altered protein degradation, autophagy pathway alterations, apoptosis, and mitochondrial dysfunction. Currently, mouse and drosophila models carrying VCP mutations provide insights into the human IBMPFD pathology and are useful as tools for preclinical studies and testing of therapeutic strategies. In this review, we will explore the pathogenesis and clinical phenotype of IBMPFD caused by VCP mutations.
123 citations
TL;DR: The hyperphosphorylated sites are similar between diseases, but filament morphologies and tau isoform compositions vary, consistent with the existence of multiple tau conformers and recent findings have provided experimental support for this concept.
Abstract: Microtubule-associated protein tau is the most commonly misfolded protein in human neurodegenerative diseases, where it becomes hyperphosphorylated and filamentous. Mutations in MAPT, the tau gene, cause approximately 5% of cases of frontotemporal dementia. They are frequently accompanied by parkinsonism. The existence of MAPT mutations has established that dysfunction of tau protein is sufficient to cause neurodegeneration and dementia. However, most tauopathies are not inherited in a dominant manner. The hyperphosphorylated sites are similar between diseases, but filament morphologies and tau isoform compositions vary. This is consistent with the existence of multiple tau conformers and recent findings have provided experimental support for this concept.
117 citations
TL;DR: Increased activation in left dorsolateral prefrontal regions that were not significantly atrophic in the authors' patient (as determined by voxel-based morphometry) is consistent with the notion that neural plasticity can support compensation for specific language loss, even in the context of progressive neuronal degeneration.
Abstract: Despite considerable recent progress in understanding the underlying neurobiology of primary progressive aphasia (PPA) syndromes, relatively little attention has been directed toward the examination of behavioral interventions that may lessen the pervasive communication problems associated with PPA. In this study, we report on an individual with a behavioral profile and cortical atrophy pattern consistent with the logopenic variant of PPA. At roughly two-and-a-half years post onset, his marked lexical retrieval impairment prompted administration of a semantically based intervention to improve word retrieval. The treatment was designed to improve self-directed efforts to engage the participant’s relatively preserved semantic system in order to facilitate word retrieval. His positive response to an intensive (2-week) dose of behavioral treatment was associated with improved lexical retrieval of items within trained categories, and generalized improvement for naming of untrained items that lasted over a 6-month follow-up interval. These findings support the potential value of intensive training to achieve self-directed strategic compensation for lexical retrieval difficulties in logopenic PPA. Additional insight was gained regarding the neural regions that supported improved performance by the administration of a functional magnetic resonance imaging protocol before and after treatment. In the context of a picture-naming task, post-treatment fMRI showed increased activation of left dorsolateral prefrontal regions that have been implicated in functional imaging studies of generative naming in healthy individuals. The increased activation in these frontal regions that were not significantly atrophic in our patient (as determined by voxel-based morphometry) is consistent with the notion that neural plasticity can support compensation for specific language loss, even in the context of progressive neuronal degeneration.
117 citations
TL;DR: By understanding PGRN in a wider context, the structure, biology, and mechanism of progranulin action may be better able to delineate its roles in the normal brain and in neurodegenerative disease.
Abstract: Mutation of human GRN, the gene encoding the secreted glycoprotein progranulin, results in a form of frontotemporal lobar degeneration that is characterized by the presence of ubiquitinated inclusions containing phosphorylated and cleaved fragments of the transactivation response element DNA-binding protein-43. This has stimulated interest in understanding the role of progranulin in the central nervous system, and in particular, how this relates to neurodegeneration. Progranulin has many roles outside the brain, including regulation of cellular proliferation, survival, and migration, in cancer, including cancers of the brain, in wound repair, and inflammation. It often acts through the extracellular signal-regulated kinase and phopshatidylinositol-3-kinases pathways. The neurobiology of progranulin has followed a similar pattern with proposed roles for progranulin (PGRN) in the central nervous system as a neuroprotective agent and in neuroinflammation. Here we review the structure, biology, and mechanism of progranulin action. By understanding PGRN in a wider context, we may be better able to delineate its roles in the normal brain and in neurodegenerative disease.
117 citations
TL;DR: A potential role for c-Abl in the pathogenesis of neurodegenerative disease is discussed, and it is attempted to place activation of c- Abl in context with other known contributors to neurodegnerative pathology.
Abstract: The c-Abl tyrosine kinase participates in a variety of cellular functions, including regulation of the actin cytoskeleton, regulation of the cell cycle, and the apoptotic/cell cycle arrest response to stress, and the Abl family of kinases has been shown to play a crucial role in development of the central nervous system. Recent studies have shown c-Abl activation in human Alzheimer’s and Parkinson’s diseases and c-Abl activation in mouse models and neuronal culture in response to amyloid beta fibrils and oxidative stress. Overexpression of active c-Abl in adult mouse neurons results in neurodegeneration and neuroinflammation. Based on this evidence, a potential role for c-Abl in the pathogenesis of neurodegenerative disease is discussed, and we attempt to place activation of c-Abl in context with other known contributors to neurodegenerative pathology.
114 citations
TL;DR: It is suggested that IGF-1R and ERK may have a role in mediating the neural stress response and the mode of action of FLX, which seems to be independent of the BDNF alterations.
Abstract: Depression is associated with hippocampus (HC) volume loss. Chronic mild stress (CMS) in rats is a model of depression. Antidepressants attenuate HC volume loss and reverse the depression-like symptoms of stressed animals. We evaluated the effect of CMS and the selective serotonin reuptake inhibitor, fluoxetine (FLX) treatment on behavioral and cognitive parameters in rats, and on HC and frontal cortex (FC) neurotrophic factors levels. Male rats were exposed sequentially, over a period of 5 weeks, to a variety of mild stressors. FLX (5 mg/kg/day ip) was administered to the stressed group and controls (unstressed). After 5 of CMS, animals were tested using the Morris Water Maze (MWM). In the MWM, we observed that FLX had a transitory effect on unstressed rats. CMS reduced insulin-like growth factor-1 receptor (IGF-1R) levels in the HC whereas after FLX treatment these levels reverted to normal range. CMS rats revealed a significant decrease in extracellular signal-regulated kinase (ERK) phosphorylation in both HC and FC regions, while FLX normalized these levels. This study suggests that IGF-1R and ERK may have a role in mediating the neural stress response and the mode of action of FLX. This role seems to be independent of the BDNF alterations.
TL;DR: These recent experiments on the nature of the toxicity of tau are reviewed with particular emphasis on experiments imaging tangles in the intact brain through a cranial window, which allows observation of tangle formation and longitudinal imaging of the fate of tangles-bearing neurons.
Abstract: Neurofibrillary tangles are intracellular accumulations of hyperphosphorylated and misfolded tau protein characteristic of Alzheimer’s disease and other tauopathies. Classic cross-sectional studies of Alzheimer patient brains showed associations of tangle accumulation with neuronal loss, synapse loss, and dementia, which led to the supposition that tangles are toxic to neurons. More recent advances in imaging techniques and mouse models have allowed the direct exploration of the question of toxicity of aggregated versus soluble tau and have surprisingly challenged the view of tangles as toxic species in the brain. Here, we review these recent experiments on the nature of the toxicity of tau with particular emphasis on our experiments imaging tangles in the intact brain through a cranial window, which allows observation of tangle formation and longitudinal imaging of the fate of tangle-bearing neurons.
TL;DR: In this article, the expression of five selected chemokine receptors, which seem to be important in cell homing, was compared and the results indicated that expression of these receptors in human mesenchymal stem cells, derived from adipose tissue, was higher than MSC from bone marrow.
Abstract: Mesenchymal stem cells (MSCs) are considered as promising candidates for new clinical trials of cell therapies. Bone marrow (BM) was the first source reported to contain MSCs; however, using it may be detrimental due to the highly invasive aspiration procedures. More recently, adipose tissue, attainable by a less invasive method, has been introduced as an alternative source of MSCs. So far, MSCs derived from these two sources have been compared in different characters; however, one of the main properties, i.e., the expression of chemokine receptors, has been ignored in these comparisons. In the present study, human MSCs were derived from bone marrow and adipose tissues and characterized by their expression of some cell surface antigens and also differentiation capacity. The expression of five selected chemokine receptors, which seems to be important in cell homing, was also compared. Semiquantitative reverse transcription-polymerase chain reaction method was used to assess gene expression levels of these chemokine receptors. Our results indicate that expression of these receptors in human MSCs, derived from adipose tissue, was higher than MSCs from bone marrow. Chemokine receptors and their ligands and adhesion molecules play an important role in tissue-specific homing of leukocytes and have also been implicated in trafficking of hematopoietic precursors into and through tissues. Therefore, MSCs from adipose tissue may show a better migration and homing capacity and they might be a better candidate for therapeutic purposes.
TL;DR: This review will summarize what is known about the cell biology of progranulin, a fascinating multifunctional protein which has been implicated in cell growth, wound repair, tumorigenesis, inflammation, neurodevelopment, and more recently in neurodegeneration.
Abstract: Progranulin is a fascinating multifunctional protein, which has been implicated in cell growth, wound repair, tumorigenesis, inflammation, neurodevelopment, and more recently in neurodegeneration. The mechanism of action of this protein is still largely unknown, but the knowledge about the cellular effects on various cell types is expanding. In the current review, we will summarize what is known about the cell biology of progranulin. A better understanding of the biology of progranulin will impact diverse areas of research.
TL;DR: It is demonstrated that the kisspeptin mRNA-expressing neurons in ARC appear earlier than those in AVPV and show clear sex differences in their numbers during neonatal period and the results indicate that the increase in kisspe leptin mRNA expression in ARC across puberty might be involved in the onset of puberty.
Abstract: Kisspeptin is a family of neuropeptides and the natural ligands of G protein-coupled receptor (GPR)-54. Kisspeptin/GPR-54 system is known to play a pivotal role in puberty onset and in the regulation of reproductive functions. To clarify the postnatal ontogeny of kisspeptin neurons in rat hypothalamus, we analyzed the expression patterns of kisspeptin mRNA from neonate to adult by in situ hybridization. In anteroventral periventricular nucleus (AVPV), kisspeptin mRNA were first detected at postnatal day (PND) 7 and postnatal week 3 in males and females, respectively, and the number of kisspeptin mRNA-expressing neurons increased during development in both sexes. In the arcuate nucleus (ARC), kisspeptin mRNA was present from PND3. In males, the number of kisspeptin mRNA-expressing neurons gradually increased during development. In females, the number of kisspeptin mRNA-expressing neurons in neonates was greater than in males; it significantly decreased at juvenile stages and then increased toward adulthood. These results indicate that the increase in kisspeptin mRNA expression in ARC across puberty might be involved in the onset of puberty. We also demonstrate that the kisspeptin mRNA-expressing neurons in ARC appear earlier than those in AVPV and show clear sex differences in their numbers during neonatal period.
TL;DR: The clinicopathologic heterogeneity in CBS/CBD and the implications of this heterogeneity on clinical practice, on understanding the focal/asymmetric cerebral degeneration syndromes, and on future research are all reviewed.
Abstract: Corticobasal degeneration (CBD) is a complex neurodegenerative disorder which nomenclature of which its nomenclature and characterization continues to evolve. The core clinical features that have been considered characteristic of the disorder include progressive asymmetric rigidity and apraxia, with other findings suggesting additional cortical (e.g., alien limb phenomena, cortical sensory loss, myoclonus, and mirror movements) and basal ganglionic (e.g., bradykinesia, dystonia, and tremor) dysfunctions. The characteristic findings at autopsy are asymmetric cortical atrophy that is typically maximal in the frontoparietal regions, as well as basal ganglia and nigral degeneration. Microscopically, abnormal accumulations of the microtubule-associated tau protein are found in both neurons and glia, and this disorder is now considered one of the “tauopathies.” CBD was initially thought to represent a distinct clinicopathologic entity. Recent studies have shown considerable clinicopathologic heterogeneity, leading some to use the term “corticobasal syndrome” (CBS) for the constellation of findings initially considered characteristic of the disorder, and the term “corticobasal degeneration” for the histopathologic disorder. In this review, the multiple phenotypes/syndromes associated with CBD pathology, and multiple diseases associated with the CBS, are presented. The clinicopathologic heterogeneity in CBS/CBD and the implications of this heterogeneity on clinical practice, on understanding the focal/asymmetric cerebral degeneration syndromes, and on future research are all reviewed.
TL;DR: It is demonstrated that α- Synuclein expression induces vulnerability to perturbations of Ypt6 and other proteins involved in retrograde endosome–Golgi transport, linking a specific trafficking defect to α-synuclein phospholipid binding.
Abstract: Parkinson’s disease is the most common neurodegenerative movement disorder. α-Synuclein is a small synaptic protein that has been linked to familial Parkinson’s disease (PD) and is also the primary component of Lewy bodies, the hallmark neuropathology found in the brain of sporadic and familial PD patients. The function of α-synuclein is currently unknown, although it has been implicated in the regulation of synaptic vesicle localization or fusion. Recently, overexpression of α-synuclein was shown to cause cytoplasmic vesicle accumulation in a yeast model of α-synuclein toxicity, but the exact role α-synuclein played in mediating this vesicle aggregation is unclear. Here, we show that α-synuclein induces aggregation of many yeast Rab GTPase proteins, that α-synuclein aggregation is enhanced in yeast mutants that produce high levels of acidic phospholipids, and that α-synuclein colocalizes with yeast membranes that are enriched for phosphatidic acid. Significantly, we demonstrate that α-synuclein expression induces vulnerability to perturbations of Ypt6 and other proteins involved in retrograde endosome–Golgi transport, linking a specific trafficking defect to α-synuclein phospholipid binding. These data suggest new pathogenic mechanisms for α-synuclein neurotoxicity.
TL;DR: A statistical association was found between DAT1 3′UTR VNTR nine repeats and PTSD, and this preliminary result confirms previous reports supporting a susceptibility role for allele 9 and PTSD.
Abstract: Posttraumatic stress disorder (PTSD) is a prevalent, disabling anxiety disorder marked by behavioral and physiologic alterations which commonly follows a chronic course. Exposure to a traumatic event constitutes a necessary, but not sufficient, factor. There is evidence from twin studies supporting a significant genetic predisposition to PTSD. However, the precise genetic loci still remain unclear. The objective of the present study was to identify, in a case–control study, whether the brain-derived neurotrophic factor (BDNF) val66met polymorphism (rs6265), the dopamine transporter (DAT1) three prime untranslated region (3′UTR) variable number of tandem repeats (VNTR), and the serotonin transporter (5-HTTPRL) short/long variants are associated with the development of PTSD in a group of victims of urban violence. All polymorphisms were genotyped in 65 PTSD patients as well as in 34 victims of violence without PTSD and in a community control group (n = 335). We did not find a statistical significant difference between the BDNF val66met and 5-HTTPRL polymorphism and the traumatic phenotype. However, a statistical association was found between DAT1 3′UTR VNTR nine repeats and PTSD (OR = 1.82; 95% CI, 1.20–2.76). This preliminary result confirms previous reports supporting a susceptibility role for allele 9 and PTSD.
TL;DR: The correlation between the increase of BTB permeability and the reduction of tight junction-related proteins suggests that LFU combined with microbubbles may be involved in the opening of the BTB by the tight junction -related proteins.
Abstract: The clinical chemotherapy of brain tumors has been limited by the blood–tumor barrier (BTB). Low-frequency ultrasound (LFU) in combination with microbubbles might be a useful method for local drug delivery. However, the underlying mechanism remains unclear. In this study, we asked whether LFU changed the permeability of BTB by regulating the tight junction-related proteins. The permeability of BTB was evaluated by Evans blue dye, and the protein and mRNA expression levels of tight junction-related proteins claudin-5, occludin, and ZO-1 were determined by immunohistochemical staining, RT-PCR, and western blot assays. We found that the permeability of BTB increased significantly after LFU exposure in the presence of Optison. The mRNA and protein expression levels of claudin-5, occludin, and ZO-1 decreased significantly at 3 h, restored gradually and nearly recovered after 12 h. The correlation between the increase of BTB permeability and the reduction of tight junction-related proteins suggests that LFU combined with microbubbles may be involved in the opening of the BTB by the tight junction-related proteins.
TL;DR: Genes linked to rare cases of familial ALS and/or FTD, like FUS, TARDBP, OPTN, and UBQLN2 may converge onto a unifying pathogenic pathway and thereby provide novel therapeutic targets common to a spectrum of etiologically diverse forms of ALS.
Abstract: Over the last couple of decades, there has been a growing body of clinical, genetic, and histopathological evidence that similar pathological processes underlie amyotrophic lateral sclerosis (ALS) and some types of frontotemporal lobe dementia (FTD). Even though there is great diversity in the genetic causes of these disorders, there is a high degree of overlap in their histopathology. Genes linked to rare cases of familial ALS and/or FTD, like FUS, TARDBP, OPTN, and UBQLN2 may converge onto a unifying pathogenic pathway and thereby provide novel therapeutic targets common to a spectrum of etiologically diverse forms of ALS and ALS–FTD. Additionally, there are major loci for ALS–FTD on chromosomes 9p and 15q. Identification of causative genetic alterations at those loci will be an important step in understanding the pathogenesis of juvenile- and adult-onset ALS and ALS–FTD. Interactions between TDP-43, FUS, optineurin, and ubiquilin 2 need to be studied to understand their common molecular pathways. Future efforts should also be directed towards generation and characterization of in vivo models to dissect the pathogenic mechanisms of these diseases. Such efforts will rapidly accelerate the discovery of new drugs that regulate accumulation of pathogenic proteins and their downstream consequences.
TL;DR: The physiological functions of the MCH system which have been investigated using MCH1R antagonists such as food intake, anxiety, depression, reward, and sleep are reviewed and some of the potential applications of MCH 1R antagonists in human disorders are suggested.
Abstract: Melanin-concentrating hormone (MCH) is a 19-amino-acid cyclic peptide which was originally found to lighten skin color in fish that is highly conserved among many species. MCH interacts with two G-protein-coupled receptors, MCH1R and MCH2R, but only MCH1R is expressed in rodents. MCH is mainly synthesized in the lateral hypothalamus and zona incerta, while MCH1R is widely expressed throughout the brain. Thus, MCH signaling is implicated in the regulation of many physiological functions. The identification of MCH1R has led to the development of small-molecule MCH1R antagonists that can block MCH signaling. MCH1R antagonists are useful not only for their potential therapeutic value, but also for understanding the physiological functions of the endogenous MCH system. Here, we review the physiological functions of the MCH system which have been investigated using MCH1R antagonists such as food intake, anxiety, depression, reward, and sleep. This will help us understand the physiological functions of the MCH system and suggest some of the potential applications of MCH1R antagonists in human disorders.
TL;DR: Imaging patterns of atrophy in bvFTD vary according to pathological diagnosis and may therefore be helpful in predicting these pathologies in b vFTD.
Abstract: Pathology underlying behavioral variant frontotemporal dementia (bvFTD) is heterogeneous, with the most common pathologies being Pick’s disease (PiD), corticobasal degeneration (CBD), and FTLD-TDP type 1. Clinical features are unhelpful in differentiating these pathologies. We aimed to determine whether imaging atrophy patterns differ across these pathologies in bvFTD subjects. We identified 15 bvFTD subjects that had volumetric MRI during life and autopsy: five with PiD, five CBD, and five FTLD-TDP type 1. Voxel-based morphometry was used to assess atrophy patterns in each bvFTD group compared to 20 age- and gender-matched controls. All three pathological groups showed gray matter loss in frontal lobes, although specific patterns of atrophy differed across groups: PiD showed widespread loss in frontal lobes with additional involvement of anterior temporal lobes; CBD showed subtle patterns of loss involving posterior lateral and medial superior frontal lobe; and FTLD-TDP type 1 showed widespread loss in frontal, temporal, and parietal lobes. Greater parietal loss was observed in FTLD-TDP type 1 compared to both other groups, and greater anterior temporal and medial frontal loss was observed in PiD compared to CBD. Imaging patterns of atrophy in bvFTD vary according to pathological diagnosis and may therefore be helpful in predicting these pathologies in bvFTD.
TL;DR: The results suggest that RLN3 is able to stimulate the hypothalamopituitary CRF–ACTH system during the acute response.
Abstract: Relaxin-3 (RLN3) is a neuropeptide belonging to the insulin–relaxin superfamily. RLN3-expressing neurons are predominantly located in the dorsal pons known as the nucleus incertus, and project their axons to the forebrain including the hypothalamus. RLN3 has been suggested to be involved in the stress response. In the present study, we investigated the hypothalamic action of RLN3 in the stress-response system by intracerebroventricular (icv) administration of RLN3. Compared with saline icv injection, 1 nmol icv RLN3 injection induced c-Fos expression in the paraventricular nucleus of the hypothalamus (PVN) at 1 h after administration. Some RLN3-induced c-Fos-positive cells in the PVN were also corticotropin-releasing factor (CRF)-expressing neurons. CRF and c-fos mRNA levels in the PVN were increased at 2 h after RLN3 administration. Plasma adrenocorticotropic hormone (ACTH) levels were also increased after RLN3 administration. These results suggest that RLN3 is able to stimulate the hypothalamopituitary CRF–ACTH system during the acute response.
TL;DR: Results indicate that DA plays a prominent role in regulating circadian activity at both behavioral and molecular levels.
Abstract: Normal circadian rhythms of behavior are disrupted in disorders involving the dopamine (DA) system, such as Parkinson’s disease. We have reported previously using unilateral injections of the catecholamine toxin, 6-hydroxydopamine (6-OHDA), into the medial forebrain bundle that DA signaling regulates daily expression of the clock protein, PERIOD2 (PER2), in the dorsal striatum of the rat. In the present study, we made widespread lesions of DA fibers using large injections of 6-OHDA into the third ventricle to determine the involvement of DA in normal daily rhythms of wheel-running activity and PER2 patterns in the suprachiasmatic nucleus (SCN) and several regions of the limbic forebrain. Rats injected with 6-OHDA and housed in constant darkness were less active in the wheel and showed a disorganized pattern of activity in which wheel running was not confined to a specific phase over 24 h. The 6-OHDA injection had no effect on the daily PER2 pattern in the SCN, but blunted the normal rise in PER2 in the dorsal striatum. 6-OHDA also blunted PER2 expression in the periventricular nucleus of the hypothalamus, a region in which a daily PER2 pattern has not been previously reported in male rats, and in the oval nucleus of the bed nucleus of the stria terminalis, but not in the central nucleus of the amygdala. These results indicate that DA plays a prominent role in regulating circadian activity at both behavioral and molecular levels.
TL;DR: The aim of this review is to highlight the key findings emerging from T DP-43 transgenic animal models and the insight they provide into the mechanisms driving TDP-43-mediated neurodegeneration.
Abstract: Since the identification of phosphorylated and truncated transactive response DNA-binding protein 43 (TDP-43) as a primary component of ubiquitinated inclusions in amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclusions, much effort has been directed towards ascertaining how TDP-43 contributes to the pathogenesis of disease. As with other protein misfolding disorders, TDP-43-mediated neuronal death is likely caused by both a toxic gain and loss of TDP-43 function. Indeed, the presence of cytoplasmic TDP-43 inclusions is associated with loss of nuclear TDP-43. Moreover, post-translational modifications of TDP-43, including phosphorylation, ubiquitination, and cleavage into C-terminal fragments, may bestow toxic properties upon TDP-43 and cause TDP-43 dysfunction. However, the exact neurotoxic TDP-43 species remain unclear, as do the mechanism(s) by which they cause neurotoxicity. Additionally, given our incomplete understanding of the roles of TDP-43, both in the nucleus and the cytoplasm, it is difficult to truly appreciate the detrimental consequences of aberrant TDP-43 function. The development of TDP-43 transgenic animal models is expected to narrow these gaps in our knowledge. The aim of this review is to highlight the key findings emerging from TDP-43 transgenic animal models and the insight they provide into the mechanisms driving TDP-43-mediated neurodegeneration.
TL;DR: Exogenous PACAP is able to counteract NMDA-induced toxicity, and that endogenous PACAP exerts a neuroprotective effect in the retina is suggested.
Abstract: Retinal excitotoxicity is one of the major causes of retinal ganglion cell (RGC) death in glaucoma. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic peptide with potent neuroprotective activity; however, whether it exerts such an effect in the retina and the mechanism by which RGCs are protected is still not well understood. In this study, we examined the effect of exogenous and endogenous PACAP on RGC death induced by N-methyl-D: -aspartate acid (NMDA). The vitreous body of anesthetized adult male mice (C57/BL6J) was injected with NMDA (40 nmol in a 2 μL saline solution). The number of RGCs decreased from days 1 to 7 after NMDA injection, and the number of dUTP end-labeling (TUNEL)-positive cells, an indicator of cell death, peaked at day 3. However, when PACAP38 (10(-8), 10(-10), 10(-12), 10(-14), or 10(-16)M) was co-administered with NMDA, the 10(-10)M dose resulted in significantly increased RGC survival at day 7, and a decrease in the number of TUNEL-positive RGCs at day 3. We next investigated the neuroprotective effect of endogenous PACAP using PACAP heterozygote(+/-) mice. Under normal circumstances, there was no significant difference in the number of RGCs in the PACAP(+/-) mice compared with their wild-type counterparts. However, the number of RGCs significantly decreased in the PACAP(+/-) mice 7 days after NMDA injection, relative to their wild-type counterparts. The number of TUNEL-positive RGCs peaked at day 1 in the PACAP(+/-) mice. These effects in the PACAP(+/-) mice were reversed by intravitreous injection of 10(-10)M PACAP38. This suggests that exogenous PACAP is able to counteract NMDA-induced toxicity, and that endogenous PACAP exerts a neuroprotective effect in the retina.
TL;DR: The mitochondrial hypothesis of sporadic, idiopathic Parkinson disease is not revised, but POLG1-related parkinsonism and other well-defined forms of “mitochondrial parkinsonisms”, with mtDNA mutations or rearrangements are reviewed.
Abstract: Mitochondrial dysfunction has been implicated in the pathogenesis of sporadic, idiopathic Parkinson disease. In some cases, mitochondrial DNA primary genetic abnormalities, or more commonly, secondary rearrangements due to polymerase gamma (POLG1) gene mutation, can directly cause parkinsonism. The case of a Parkinson disease patient with some signs or symptoms suggestive of mitochondrial disease (i.e., ptosis, myopathy, neuropathy) is a relatively common event in the neurological practice. Mitochondrial parkinsonisms do not have distinctive features allowing an immediate diagnosis, and a negative family history does not rule out a possible diagnosis of mitochondrial disorder. In this article, we do not revise the mitochondrial hypothesis of sporadic, idiopathic Parkinson disease, extensively discussed elsewhere, but we review POLG1-related parkinsonism and other well-defined forms of “mitochondrial parkinsonisms”, with mtDNA mutations or rearrangements. Lastly, we try to introduce a possible diagnostic approach for patients with parkinsonism and suspected mitochondrial disorder.
TL;DR: Accumulating evidence suggests that TDP-43 abnormal cellular aggregation causes a possible gain of function, also suggested by recently constructed mouse models of T DP-43 proteinopathy; however, it would be inconvincible that sequestration of physiological TSPs within cellular aggregates observed in patients would be innocuous for disease pathogenesis.
Abstract: Loss-of-function mutations in the multifunctional growth factor progranulin (GRN) cause frontotemporal lobar degeneration (FTLD) with TDP-43 protein accumulation. Nuclear TDP-43 protein with key roles in RNA metabolism is also aggregated in amyotrophic lateral sclerosis (ALS), suggesting that ALS and FTLD constitute a broad disease continuum. However, the fact that mutations in GRN are associated with FTLD, while mutations in TDP-43 cause a preferential loss of motor neurons resulting in ALS-end of the disease spectrum, suggests involvement of both cell-autonomous and non-autonomous mechanisms. Studies on animal models and in vitro studies have been instrumental in understanding the link between GRN and TDP-43 and also their role in neurodegeneration. For instance, in mouse models, allelic deficiencies of Grn do not recapitulate human pathology of TDP-43 brain accumulations, but embryonic neurons derived from these mice do show abnormal TDP-43 accumulation after additional cellular challenges, suggesting that TDP-43 changes observed in GRN mutation carriers might also relate to stress. Recent results have shown that the dual action of GRN in growth modulation and inflammation could be due to its negative regulation of TNF-α signaling. In addition, GRN also interacts with sortilin and is endocytosed, thereby regulating its own levels and possibly also modulating the turnover of other proteins including that of TDP-43. Accumulating evidence suggests that TDP-43 abnormal cellular aggregation causes a possible gain of function, also suggested by recently constructed mouse models of TDP-43 proteinopathy; however, it would be inconvincible that sequestration of physiological TDP-43 within cellular aggregates observed in patients would be innocuous for disease pathogenesis. This review discusses some of these data on the possible link between GRN and TDP-43 as well as mechanisms involved in TDP-43-led neurodegeneration. Continued multitiered efforts on genetic, cell biological, and animal modeling approaches would prove crucial in finding a cure for GRN-related diseases.
TL;DR: Results suggest that blockade of NMDA receptors by sub-chronic PCP administration has a long-lasting down-regulatory effect on BDNF mRNA expression in the female rat brain which may underlie some of the behavioural deficits observed post PCP treatment.
Abstract: Phencyclidine (PCP), used to mimic certain aspects of schizophrenia, induces sexually dimorphic, cognitive deficits in rats. In this study, the effects of sub-chronic PCP on expression of brain-derived neurotrophic factor (BDNF), a neurotrophic factor implicated in the pathogenesis of schizophrenia, have been evaluated in male and female rats. Male and female hooded-Lister rats received vehicle or PCP (n = 8 per group; 2 mg/kg i.p. twice daily for 7 days) and were tested in the attentional set shifting task prior to being sacrificed (6 weeks post-treatment). Levels of BDNF mRNA were measured in specific brain regions using in situ hybridisation. Male rats were less sensitive to PCP-induced deficits in the extra-dimensional shift stage of the attentional set shifting task compared to female rats. Quantitative analysis of brain regions demonstrated reduced BDNF levels in the medial prefrontal cortex (p < 0.05), motor cortex (p < 0.01), orbital cortex (p < 0.01), olfactory bulb (p < 0.05), retrosplenial cortex (p < 0.001), frontal cortex (p < 0.01), parietal cortex (p < 0.01), CA1 (p < 0.05) and polymorphic layer of dentate gyrus (p < 0.05) of the hippocampus and the central (p < 0.01), lateral (p < 0.05) and basolateral (p < 0.05) regions of the amygdaloid nucleus in female PCP-treated rats compared with controls. In contrast, BDNF was significantly reduced only in the orbital cortex and central amygdaloid region of male rats (p < 0.05). Results suggest that blockade of NMDA receptors by sub-chronic PCP administration has a long-lasting down-regulatory effect on BDNF mRNA expression in the female rat brain which may underlie some of the behavioural deficits observed post PCP administration.
TL;DR: The results suggest that MTNR1A may be a susceptibility gene for schizophrenia and may be associated with insomnia symptoms exhibited in schizophrenia patients, and rs4753426 ofMTNR1B was not associated with either schizophrenia or clinical phenotypes.
Abstract: Schizophrenia patients commonly have sleep disturbances. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in the promoter region of the melatonin receptor genes (MTNR1A and MTNR1B) were associated with schizophrenia and with sleep problems such as insomnia and hypersomnia in schizophrenia patients. We genotyped two promoter SNPs [rs2119882 (−184T/C) of MTNR1A and rs4753426 (−1193C/T) of MTNR1B] using direct sequencing in 289 schizophrenia patients and 505 control subjects. We found that rs2119882 of MTNR1A was associated with schizophrenia in recessive model [CC vs. TT/TC, p = 0.013, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.12–2.55]. Interestingly, in an analysis of clinical phenotypes, we found that rs2119882 of MTNR1A was also associated with insomnia symptoms of schizophrenia (recessive model, p = 0.010, OR = 2.24, 95% CI = 1.21–4.14), but not with hypersomnia symptoms as determined using the Operational Criteria checklist. However, rs4753426 of MTNR1B was not associated with either schizophrenia or clinical phenotypes. Our results suggest that MTNR1A may be a susceptibility gene for schizophrenia and may be associated with insomnia symptoms exhibited in schizophrenia patients.