Toshihiro Masaki

Reprogramming Adult Schwann Cells to Stem Cell-like Cells by Leprosy Bacilli Promotes Dissemination of Infection

Differentiated cells possess a remarkable genomic plasticity that can be manipulated to reverse or change developmental commitments. Here, we show that the leprosy bacterium hijacks this property to reprogram adult Schwann cells, its preferred host niche, to a stage of progenitor/stem-like cells (pSLC) of mesenchymal trait by downregulating Schwann cell lineage/differentiation-associated genes and upregulating genes mostly of mesoderm development. Reprogramming accompanies epigenetic changes and renders infected cells highly plastic, migratory, and immunomodulatory. We provide evidence that acquisition of these properties by pSLC promotes bacterial spread by two distinct mechanisms: direct differentiation to mesenchymal tissues, including skeletal and smooth muscles, and formation of granuloma-like structures and subsequent release of bacteria-laden macrophages. These findings support a model of host cell reprogramming in which a bacterial pathogen uses the plasticity of its cellular niche for promoting dissemination of infection and provide an unexpected link between cellular reprogramming and host-pathogen interaction.

Association study of brain-derived neurotrophic factor gene polymorphism and alcoholism.

OBJECTIVE Brain-derived neurotrophic factor (BDNF) influences dopamine and serotonin neurotransmitters that are heavily linked to addiction. A quantitative trait loci study indicated that genes localized to 11p13, where the BDNF gene is mapped (11p13-15), increase the risk for severe alcohol withdrawal. Moreover, a recent study using a pooled-sample microarray suggested that the BDNF gene locus was included in the loci that were shown to be associated with drug abuse. These lines of evidence suggested that BDNF might play some role in the development of or vulnerability to alcoholism and/or clinical characteristics of alcoholic individuals. METHODS The alcoholic subjects consisted of 377 male Japanese patients. A structured interview was used to obtain social background, drinking history, history of violence while intoxicated, history of alcohol withdrawal, and family history of alcoholism. The control group consisted of 336 nonalcoholic male subjects. Genotyping of the G196A polymorphism of the BDNF gene was done by polymerase chain reaction (PCR)-restriction fragment length polymorphism method. RESULTS Genotype and allele distributions of the BDNF gene polymorphism did not differ significantly between alcoholic and control subjects. However, comparing clinical characteristics across G196A genotypes, we found that alcoholic subjects with violent tendencies and a history of delirium tremens had a significantly higher frequency of AA genotypes and A allele frequencies than those without them. Moreover, alcoholic subjects with the A allele had earlier onset of the disease than those without it. CONCLUSIONS These results indicate that BDNF gene polymorphism might modify phenotypes of alcoholism.

Characterization of the Transmembrane Molecular Architecture of the Dystroglycan Complex in Schwann Cells

We have demonstrated previously 1) that the dystroglycan complex, but not the sarcoglycan complex, is expressed in peripheral nerve, and 2) that α-dystroglycan is an extracellular laminin-2-binding protein anchored to β-dystroglycan in the Schwann cell membrane. In the present study, we investigated the transmembrane molecular architecture of the dystroglycan complex in Schwann cells. The cytoplasmic domain of β-dystroglycan was co-localized with Dp116, the Schwann cell-specific isoform of dystrophin, in the abaxonal Schwann cell cytoplasm adjacent to the outer membrane. β-dystroglycan bound to Dp116 mainly via the 15 C-terminal amino acids of its cytoplasmic domain, but these amino acids were not solely responsible for the interaction of these two proteins. Interestingly, the β-dystroglycan-precipitating antibody precipitated only a small fraction of α-dystroglycan and did not precipitate laminin and Dp116 from the peripheral nerve extracts. Our results indicate 1) that Dp116 is a component of the submembranous cytoskeletal system that anchors the dystroglycan complex in Schwann cells, and 2) that the dystroglycan complex in Schwann cells is fragile compared with that in striated muscle cells. We propose that this fragility may be attributable to the absence of the sarcoglycan complex in Schwann cells.

Influence of Genetic Variations of Ethanol‐Metabolizing Enzymes on Phenotypes of Alcohol‐Related Disorders

Abstract: Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase‐2 (ALDH2) play central roles in the metabolism of ethanol and its metabolite, acetaldehyde, in the liver. In ADH2, one nucleotide replacement causes either a super‐active beta 2 subunit encoded by the ADH2*2 allele or a less active beta 1 subunit (ADH2*1 allele). In the same way, a G/A replacement at codon 487 of the ALDH2 gene produces an inactive form of the enzyme. Because the geno‐types of these genes may explain individual differences in concentration and elimination of ethanol and acetaldehyde in the blood after drinking, they could be used as models to elucidate the contribution of these substances to the development of addiction and various types of organ damage. We have examined the influence of genetic variations of these enzymes on alcohol‐related disorders in the Japanese. The results revealed that (1) the less active allele of the ADH2 gene (ADH2*1) is associated with an increased risk for alcohol dependence, alcohol‐induced persistent amnestic disorder, alcohol withdrawal syndrome, and cancer of the upper GI tract; (2) the inactive allele of the ALDH2 gene (ALDH2*2) is associated with a decreased risk for alcohol dependence, and an increased risk for alcoholic polyneuropathy and cancer in the same region; and (3) these genetic variations modify clinical features of alcohol dependence. Possible mechanisms of altered risk for these disorders are discussed.

Multicatalytic proteinase is present in Lewy bodies and neurofibrillary tangles in diffuse Lewy body disease brains

A non-lysosomal multicatalytic proteinase (MCP) is immunohistochemically visualized in Lewy bodies and loosely arranged globose tangles but not in the majority of compact neurofibrillary tangles in brains with cortical diffuse Lewy body disease. Virtually all Lewy bodies are immunoreactive to MCP, exhibiting various staining patterns where they are moderately diffuse, intense in the central core or intense in the peripheral rim. MCP may be involved in the formation of these inclusions.

Benign type of central pontine myelinolysis in alcoholism: Clinical, neuroradiological and electrophysiological findings

Abstract.Nine alcoholic patients with central pontine myelinolysis (CPM),who showed a favorable prognosis, are reported. The majority of them had taken part in binge drinking and had a subsequent consciousness disturbance for 18.1±10.9 (mean±SD) days. None of the patients had had acute correction of hyponatremia. Truncal ataxia and gait instability were present in most of the patients after recovery from the disturbance of consciousness. Most of them eventually gained independence, and magnetic resonance imaging showed that their pontine lesions tended to shrink. Electrophysiological studies detected prolonged latency between the I and III waves in auditory brainstem responses and between N11 and P13/14 onsets in the somatosensory evoked potentials. These clinical, radiological and electrophysiological findings should be of use in diagnosing CPM.

Atypical MRI features of Wilson's disease : high signal in globus pallidus on T1-weighted images

Abstract Most reports of MRI in Wilsons disease have been of abnormal low-signal lesions on T1-weighted images and high signal intensity on T2-weighted images. In contrast, we report three patients who had high-signal lesions in the globus pallidus on T1-weighted images, a finding seen in patients with portal-systemic encephalopathy. The possible causes include the paramagnetic effect of copper or iron and accumulation of Alzheimer type II glial cells.

Expression of dystroglycan and laminin-2 in peripheral nerve under axonal degeneration and regeneration

Abstract In Schwann cells, the transmembrane glycoprotein β-dystroglycan composes the dystroglycan complex, together with the extracellular glycoprotein α-dystroglycan which binds laminin-2, a major component of the Schwann cell basal lamina. To provide clues to the biological functions of the interaction of the dystroglycan complex with laminin-2 in peripheral nerve, the expression of β-dystroglycan and laminin-α2 chain was studied in rat sciatic nerves undergoing axonal degeneration and regeneration as well as in normal condition. In normal sciatic nerve, immunoreactivity for the cytoplasmic domain of β-dystroglycan was consistently and selectively localized in the Schwann cell cytoplasm underlying the outer (abaxonal) membrane apposing the basal lamina. While β-dystroglycan expression was gradually down-regulated in Schwann cells losing contact with axons during axonal degeneration, it was progressively up-regulated as the regenerating process of ensheathment and myelination proceeded during regeneration. Interestingly, β-dystroglycan expression, when detectable, was always restricted to the Schwann cell cytoplasm beneath the outer membrane apposing the basal lamina during both axonal degeneration and regeneration. Furthermore, laminin-α2 immunoreactivity roughly paralleled that of β-dystroglycan during both axonal degeneration and regeneration, indicating that the expression of β-dystroglycan and laminin-α2 is induced and maintained by the Schwann cell contact with axons. Our results indicate that the dystroglycan complex is involved in the adhesion of the Schwann cell outer membrane with the basal lamina and suggest that the dystroglycan complex may play a role in the process of Schwann cell ensheathment and myelination through the interaction with laminin-2.

Association between a polymorphism of brain-derived neurotrophic factor gene and sporadic Parkinson's disease

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Defective peripheral nerve myelination and neuromuscular junction formation in fukutin-deficient chimeric mice

Dystroglycan is a central component of the dystrophin–glycoprotein complex that links the extracellular matrix with cytoskeleton. Recently, mutations of the genes encoding putative glycosyltransferases were identified in several forms of congenital muscular dystrophies accompanied by brain anomalies and eye abnormalities, and aberrant glycosylation of α‐dystroglycan has been implicated in their pathogeneses. These diseases are now collectively called α‐dystroglycanopathy. In this study, we demonstrate that peripheral nerve myelination is defective in the fukutin‐deficient chimeric mice, a mouse model of Fukuyama‐type congenital muscular dystrophy, which is the most common α‐dystroglycanopathy in Japan. In the peripheral nerve of these mice, the density of myelinated nerve fibers was significantly decreased and clusters of abnormally large non‐myelinated axons were ensheathed by a single Schwann cell, indicating a defect of the radial sorting mechanism. The sugar chain moiety and laminin‐binding activity of α‐dystroglycan were severely reduced, while the expression of β1‐integrin was not altered in the peripheral nerve of the chimeric mice. We also show that the clustering of acetylcholine receptor is defective and neuromuscular junctions are fragmented in appearance in these mice. Expression of agrin and laminin as well as the binding activity of α‐dystroglycan to these ligands was severely reduced at the neuromuscular junction. These results demonstrate that fukutin plays crucial roles in the myelination of peripheral nerve and formation of neuromuscular junction. They also suggest that defective glycosylation of α‐dystroglycan may play a role in the impairment of these processes in the deficiency of fukutin.