Ministry of Education, Culture, Sports, Science and Technology: Grant-in-Aid for Scientific Research on Innovative Areas - Foundation of Synapse and Neurocircuit Pathology

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Research [Circuit Pathology]

Projects Planned for Research Area

Nukina Group

Project Title Development of analysis approach for the selective neuronal pathology

Why the certain neuronal system degenerates is the most important and difficult question in the field of neurodegenerative disorders. To elucidate this subject in Huntington disease (HD), we established several transgenic mouse lines, which express fluorescent protein in medium spiny neurons under the control of some promoters. Using those mice, we will develop the method for detecting specific features in certain neuronal group. By crossing polyglutamine model mice with these mice, we will detect the changes of specific neuronal group by polyglutamine accumulation. Furthermore, the effect of a highly dysregulated gene in the striatum of HD will be analyzed using specific knockout mouse.

Katsuno Group

Project Title Elucidation of molecular pathogenesis in motor neurocircuit degeneration and development of therapy for motor neuron diseases

Selective loss of motor neurons is the fundamental histopathological feature of motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA), but neither molecular basis nor therapy for motor neurocircuit degeneration in these disorders has been established. The aim of this study is to elucidate the common pathomechanism underlying selective motor neuron degeneration in ALS and SBMA, with a special interest in cellular signaling such as TGF-beta, NFkB, and JNK. We will also develop molecular-targeted therapies that prevent selective neurodegeneration in motor neuron diseases.

Publicly Invited Research (H25-26)

Sadakata Group

Project Title Analyses of a mouse model of developmental disorder.

CAPS2 is a protein that is essential for the depolarization-dependent release of BDNF and neurotrophin-3 (NT-3) from cerebellar granule cells. We previously identified a rare alternative splice variant of CAPS2, termed dex3, that is overrepresented in patients with autism and is missing exon 3, which is critical for the axonal localization of the protein. We recently reported that a mouse expressing dex3, Caps2Δex3/Δex3, exhibits autistic-like behavioral phenotypes. Moreover, we recently found that the dex3 mice showed developmental abnormalities, including a deficit in the dendritic arborization of Purkinje cells, impaired formation of vermian lobules and fissures, and delayed proliferation of granule cell precursors. We will try to elucidate whether the cerebellar phenotypes of dex3 mice are related to the onset of autism.

Yamanashi Group

Project Title Study on the dying-back pathology in ALS models

ALS is a fatal disease characterized by progressive degeneration of motor neurons with unknown etiology. Recent studies with animal models and clinical samples demonstrated "dying-back" pattern of motor nerve degeneration, which begins from the presynaptic region of neuromuscular junction. Our goal is to understand the molecular bases of "dying-back" pattern of motor neuron pathology as a path toward uncovering therapeutic targets.

Onodera Group

Project Title U12 type splicing and ALS circuit pathology

The identification of TAR DNA binding protein (TDP-43) accelerates the research for Amyotrophic lateral sclerosis (ALS). However the motor system selectivity of ALS is still obscure. To reveal the molecular mechanism for this circuit pathology, we have to elucidate the following things: 1) the selectivity in the motor system for TDP-43 pathology; 2) the vulnerability of motor neuron. The selectivity in motor neuron system may be explained the cell specific metabolism of TDP-43. The vulnerability of motor neuron may be explained by the U12 type splicing. We investigate these factors in this project.

Takada Group

Project Title Circuit pathology of Parkinson’s disease that distinguish between motor and cognitive deficits

It is thought that nigrostriatal dopamine pathways consist of two distinct circuits based on their topographic arrangement, each of which is involved specifically in motor or cognitive functions. The motor-related circuit arises from the lateral nigra and terminates within the posterior putamen, whereas the cognition-related circuit originates from the medial nigra and reaches the anterior putamen and the caudate nucleus. Using pathway-selective gene transfer techniques with viral vectors, we have recently established novel approaches to express functional molecules in nigral dopamine neurons that induce cell death or activity suppression. By means of these techniques, the present study aims at developing and analyzing primate models for Parkinson’s disease that distinguish between motor and cognitive deficits, to elucidate the circuit pathology of the disease.

Yamashita Group

Project Title Elucidation of the molecular mechanism of axonal degeneration

Degenerative phenomena of nerve axons are found in neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease, suggesting that the aggravation of neurological symptoms due to neurodegenerative diseases can be stopped by appropriately controlling axonal degeneration. However, little is known about the underlying mechanism thereof. In this study, we will attempt an approach from the perspective of axonal degeneration programs induced by exogenous and endogenous causes, will examine the overall picture of the molecular mechanisms of the formation of degenerative phenomena, and will proceed with a strategy to search an effective site of action. Our purpose is to elucidate the mechanism of degenerative phenomena affecting nerve axons in neurodegenerative diseases on the basis of the basic research findings obtained from this study, and ultimately, to develop therapeutic methods which effectively inhibit axonal degeneration and promote the repair of neural circuits.

Kawahara Group

Project Title Elucidation of a common pathogenic role of Ataxin-2 in ALS and SCA2

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease. The disorder is caused by abnormal CAG repeat expansion in the coding region of the Ataxin-2 gene (ATXN2). Recently, moderate CAG repeat expansion in ATXN2 was identified as a risk factor for amyotrophic lateral sclerosis (ALS). This finding suggests a common pathogenic role of Ataxin-2 in these neurodegenerative diseases. Therefore, a comprehensive understanding of the physiological functions of Ataxin-2, especially related to disease pathogenesis, is necessary to elucidate the mechanism underlying Ataxin-2-mediated neurodegeneration. In this study, we aim to elucidate how abnormally expanded polyglutamine tract affects the physiological functions of Ataxin-2 and induce neurodegeneration for the establishment of the therapeutic targets in the future.

Satake Group

Project Title Elucidation of synaptic and neuronal circuit of pathology in Parkinson’s disease using genomic approaches.

Pathology of synapse and neuronal circuits is a key to the onset and progress of Parkinson’s disease. In order to identify rare variants with large effect size on the onset of sporadic PD, we will perform whole exome sequencing by using next generation sequencing technology. Through analysis of synapse-related genes specifically, we aim to elucidate synaptic pathology of PD from a genomic view point. In addition, by generating and analyzing transgenic flies as an in vivo model of PD, we aim to elucidate roles of the newly identified PD-associated genes in pathogenesis of the disease. Furthermore, genetic networks of these novel PD-associated genes will be investigated in vivo. Through the aforementioned approaches, we aim to elucidate synaptic/neuronal circuits of the pathology of sporadic PD.

Nakabeppu Group

Project Title Dual effects of galectin-1 in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal disease which shows progressive muscle weakness associated with degeneration of motor neurons. While majority of ALS patients are sporadic, 5% or greater of all cases run in families. In both sporadic and familial ALS (FALS), the presence of axonal spheroids and perikaryal accumulations/aggregations comprised of the neuronal intermediate filament proteins, neurofilaments and peripherin is one of the pathological hallmarks, however, it is largely unknown how these abnormalities occur and what their precise contribution is to the pathogenesis of ALS. Among proteins encoded by genes responsible for FALS, ubiquitin-2, SOD1, FUS, TDP-43, and/or OPTN proteins are known to be accumulated in the abnormal structures as are neurofilaments and peripherin whose mutations have been identified in sporadic ALS cases. Galectin-1, a member of β-galactoside-binding lectins, is another component accumulating in the abnormal structures in both sporadic and familial ALS patients, however, its mutation has not been identified and the role of galectin-1 in the pathogenesis of ALS remains unknown. In the present study, we examine roles of galectin-1 in the pathogenesis of ALS using the ALS model mice (SOD1G93A) and galectin-1 null mice (Lgals1-/-) in order to elucidate the molecular mechanism underlying the pathogenesis of ALS.

Wake Group

Project Title The neural circuit basis of schizophrenia mouse model

The aim of this project is to understand the neural basis of the schizophrenia on the circuit level. We used the schizophrenia mouse model combined with the 2 photon microscope and adeno-associated virus injection which coded genetically encoded calcium indicators to visualize the neural activity. Visualization of the neural activity during the motor learning task reveals the difference of the firing pattern of each neuron over the days and lead us to understand the circuit abnormalities. Furthermore, we used the electrophysiological technique to study the input output ratio of the single neuron. We would like to conclude the abnormal behavior phenotype as a result of the difference of firing pattern and of single neuronal properties in schizophrenia mouse model.

Isa Group

Project Title Identifying the neural circuit for functional recovery after the spinal cord injury and development of novel therapeutic strategies to facilitate the recovery.

After the partial spinal cord injury, the impaired limb movements could partly be compensated by the function of residual neural circuits which spared the injury. We found that even if the corticospinal tract was transected at the midcervical (C5) level, dexterous digit movements such as precision grip was once impaired but could recover in 1-2 months through rehabilitative training in macaque monkeys. We obtained experimental results which suggested that the propriospinal neurons (PNs) with cell bodies in the mid-cervical segments were involved in the functional recovery but the evidence was still indirect and not clear-cut. In this project, we will apply the pathway-selective and reversible transmission blocking technique to the PNs and demonstrate the involvement of the PNs in the functional recovery after the CST lesion. In this method, neurons which were double infected by the highly efficient retrograde gene transfer vector and adenoviral vector are targeted. In addition, we will introduce a variety of growth factors to the PNs by such pathway-selective genetic manipulation technique and develop "the pathway-targeted gene therapy" to facilitate the recovery from spinal cord injury.

Hasegawa Group

Project Title Molecular mechanisms of abnormal protein aggregation in neurodegen-erative diseases

Cytoplasmic inclusions composed of misfolded proteins in neuronal and/or glial cells are common neuropathological features of most neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), FTLD, and ALS. We investigate the molecular mechanisms underlying these protein deposits, propagation of abnormal proteins (tau, alpha-synuclein and TDP-43), and neurodegeneration, by analyzing these abnormal proteins in brains of patients and by developing cellular and animal models.

Hoshino Group

Project Title Identification and analysis of the responsible gene for epilepsy caused by malformed neurocircuitry

Genetically epileptic model rats, Ihara epileptic rat (IER), have neuropathologic abnormalities, exhibit features of mental retardation at two months after birth, and develop generalized convulsive seizures when they reach the age of 3-5 months. In this study, we will identify the causative gene for IER and investigate its function in the normal neurocircuit formation. We also clarify how convulsion occurs in IER by anatomical, physiological, cell biological and genetic analyses. In addition, we will try to identify a group of human epilepsy which is caused by dysfunction of the gene.

Publicly Invited Research (H23-24)

Imai Group

Project Title Comprehensive analysis of the protein network for a late-onset Parkinson’s disease gene product

Parkinson’s disease (PD) is characterized by an age-dependent neurodegeneration of the midbrain dopaminergic neurons. The LRRK2 gene, one of the major genetic causes of PD, encodes a kinase with multiple functional domains. Pathogenic mutations in LRRK2 gradually lead to regression and degeneration of axons over a long period of time. Although the neuropathological features of PD with LRRK2 are quite similar to those of typical PD, the neuropathological mechanism is almost unknown. Our research will attempt to clarify the LRRK2 protein network and the pathological mechanism of axon degeneration caused by LRRK2 mutations using a combination of proteomics and Drosophila genetics.

Nishitoh Group

Project Title Identification of the molecular mechanism of motor neuron dysfunction in ALS

Amyotrophic lateral sclerosis (ALS) is caused by the selective motor neuron dysfunction. Since mutation in SOD1 was found to be responsible for familial ALS in 1993, a number of researches have been done. However, a common mechanism to explain the pathogenesis of all ALS including sporadic ALS remains unrevealed. There is still no molecular mechanism based treatment for ALS. We previously reported that three representative SOD1 mutants (A4V, G85R, and G93A) interact directly and specifically with Derlin-1, a component of the endoplasmic reticulum-associated degradation (ERAD) machinery. This interaction triggers ER stress through the disruption of ERAD and eventually contributes to motor neuron death. In this research, we intend to elucidate the mechanism in which the SOD1 mutant-Derlin1 interaction-induced ER stresses exhibit the motor neurotoxicity during the intercellular communication surrounding motor neuron.

Yokota Group

Project Title Investigation of TDP-43 pathology using monkey model and ALS patients materials

With overexpression of wild-type TDP-43 in spinal cord of cynomolgus monkeys, we showed  that monkeys developed progressive motor weakness and muscle atrophy with fasciculation initiated by distal hand muscles, remi niscent of ALS patients. Monkeys produced regional cytoplasmic TDP-43 mislocalization with loss of nuclear TDP-43 staining. There is species difference in TDP-43 pathology, and our monkey model recapitulates ALS pathology much better than rodent model. In addition, the dermal cells in ALS patients skin showed increased expression of TDP-43 on immunohistochemical analysis.
Using this model monkey and ALS patients skin material, we will investigate the focal and general gene analysis of TDP pathology.

Takada Group

Project Title Circuit pathology of Parkinson’s disease that discriminates between motor and cognitive impairments

According to previous anatomical and physiological findings, it can be considered that there exist two topographically-separate nigrostriatal dopamine pathways, each of which is involved specifically in motor or cognitive functions. The motor-related pathway arises from the lateral nigra and terminates within the posterior putamen, whereas the cognition-related pathway originates from the medial nigra to reach the anterior putamen and the caudate nucleus. Using an HIV-1-based lentiviral vector with enhanced retrograde transfer and an adeno-associated viral vector, we have recently established a pathway-selective gene expression technique with Cre-loxP site-specific recombination. By means of this technique, the present study aims at developing and analyzing a novel primate model for Parkinson’s disease that discriminates between motor and cognitive impairments, to elucidate the circuit pathology of the disease.

Ikenaka Group

Project Title Crosstalk between microglia and oligodendrocyte mediated by cystatin F, and its significance in demyelinating diseases.

In human demyelinating diseases, demyelinating lesions do not occur in all the neuronal circuits. Also in some of the mouse demyelination models, demyelinating lesions do not appear in all the circuits but rather in a certain neuronal circuit. Demyelinating lesions are formed not only by degeneration of myelin sheath but also by the inhibition of myelin regeneration. Our previous studies demonstrated that myelin regeneration is heavily dependent on the presence of cystatin F produced by microglia. In the current study we will clarify how the expression of cystatin F is regulated in specified microglial population in a neuronal circuit dependent manner.

Sadakata Group

Project Title Pervasive developmental disorder analysis using the model mouse

Ca2+-activated protein for secretion 2 (CAPS2) promotes secretion of brain-derived neurotrophic factor (BDNF) from dense-core vesicles. We have previously reported that CAPS2 knockout mice show impaired adaptation to novel environments (Sadakata et al., J. Clin. Invest., 2007), which is analogous to an autistic symptom. We have also shown that some autistic patients have abnormally high levels of an exon-3-skipped CAPS2 splice variant, which is defective in axonal transport. I have already succeeded in generating exon-3-skipped CAPS2 mice and have started to examine their behavioral phenotypes. CAPS2Δexon 3 mice show augmented anxiety in unfamiliar environments, impaired social functioning, abnormal sleep-wake rhythm, and some other autistic-like phenotypes. My preliminary data has also confirmed that exon-3-skipped CAPS2 proteins are not transported to axons but are accumulated in cell bodies. I will try to clarify in detail the genetic association of CAPS2 with autism.

Hasegawa Group

Project Title Intracellular amyloid-like protein and neurodegeneration of specific neural networks

Intracellular amyloid-like protein deposition is a common neuropathological feature of many neurodegenerative diseases. Importantly, the extent of the abnormal protein pathologies is closely correlated with the disease progression. We have proposed as a hypothesis that neurodegenerative diseases with amyloid-like proteins can be regarded as “protein cancers”. In this project, we will demonstrate that intracellular amyloid-like proteins, such as tau, alpha-synuclein, and TDP-43, propagate from cell to cell and this propagation is the cause of disease progression, analogously to metastasis of cancer cells to multiple different tissues in cancer progression. We also investigate the drugs and clinical therapy for the diseases by regulating the propagation of abnormal proteins.

Hoshino Group

Project Title Identification and analysis of a responsible gene for epilepsy caused by malformed neurocircuitry

Genetically epileptic model rats, Ihara epileptic rat (IER), have neuropathologic abnormalities, exhibit features of mental retardation at two months after birth, and develop generalized convulsive seizures when they reach the age of 3~5 months. In this study, we will identify the causative gene for IER and investigate its function in the normal neurocircuit formation. We also clarify how convulsion occurs in IER by anatomical, physiological, cell biological and genetic analyses. In addition, we will try to identify a group of human epilepsy which is caused by malfunction of the gene.

Yamashita Group

Project Title Investigation of molecular mechanism of axon degeneration

Axonal degeneration is a crucial event resulting in impaired neural function in a wide variety of neurodegenerative diseases, suggesting that regulation of axonal degeneration is clinically important. Supporting this notion, our recent findings indicate that inhibiting JNK was effective in blocking axonal degeneration caused by spinal cord injury and enhanced recovery of motor function. We aim to elucidate the molecular mechanism underlying axonal degeneration by focusing on the intrinsic and extrinsic factors that can induce it. Through this approach, we will try to unveil the whole body of the program of induction of axonal degeneration. This study would contribute to finding efficient molecular targets to block the axonal degeneration signals and to enhancing restoration of the neural circuit.

Kawata Group

Project Title The effect of steroid hormones (corticoids, androgen, estrogen, progesterone) during critical periods on the stress response and sexual behaviors of adults: their regulatory mechanism and disorder

The effects of hormones determine development of the nervous tissue and behavioral regulation during critical periods. Steroid hormones from adrenal and gonads enter the brain without the regulation of blood-brain-barrier because of their chemical properties. The project is aimed to elucidate the effects of steroid hormones at prenatal and postnatal critical periods on the adult stress response and sexual behavior in connection with the expression of specific peptides, steroid hormones receptors. Special attention will be paid to the involvement of epigenetic action, versatility of PTSD animal model and some transgenic mice of glutamate receptor from behavioral neuroendocrine points of view.

Collaborators

Takahashi Group

Hikida Group

Project Title Analysis of the basal ganglia neurocircuit pathology of neuropsychiatric disorders using reversible neurotransmission blocking technique

Dysfunction of the basal ganglia leads to neuropsychiatric disorders such as Parkinson’s disease, drug addiction, PTSD, depression, and schizophrenia.  However, the neurocircuit pathology of these neuropsychiatric disorders was unknown.  We have developed reversible neurotransmission blocking (RNB) of the direct or indirect pathway in the basal ganglia circuit in vivo, and revealed the distinct role of the direct and indirect striatal pathways in reward and aversive behavior (Hikida et al., Neuron, 2010).  In this research project, we will apply this RNB technique with the mouse models of neuropsychiatric disorders to reveal the basal ganglia neurocircuit pathology of these neuropsychiaric disorders.

Yamanaka Group

Project Title Elucidating the mechanisms of motor neuron degeneration through dysregulated neuron-glia network.

Non-neuronal cells have recently been recognized as important components in the neurodegenerative diseases. Using inherited motor neuron disease models, we focus on elucidating the molecular machineries dysregulated within microglia, which we previously identified as a determinant of disease progression. We will analyze the dysregulated genes in microglial cells using in vitro system including primary glial culture. Based on the results, we plan to perform the experiments to treat the motor neuron disease rodent models by controlling the action of microglial cells, contributing to the mission of this innovative research area of “circuit pathology”.

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