Yoko Aburakawa

Effects of antidepressants on GluR2 Q/R site-RNA editing in modified HeLa cell line.

Marked reduction of RNA editing at the glutamine (Q)/arginine (R) site of the glutamate receptor subunit type 2 (GluR2) in motor neurons may be a contributory cause of neuronal death specifically in sporadic ALS. It has been shown that deregulation of RNA editing of several mRNAs plays a causative role in diseases of the central nervous system such as depression. We analyzed the effects of eight antidepressants on GluR2 Q/R site-RNA editing in a modified HeLa cell line that stably expresses half-edited GluR2 pre-mRNA. We also measured changes in RNA expression levels of adenosine deaminase acting on RNA type 2 (ADAR2), the specific RNA editing enzyme of the GluR2 Q/R site, and GluR2, in order to assess the molecular mechanism causing alteration of this site-editing. The editing efficiency at the GluR2 Q/R site was significantly increased after treatment with seven out of eight antidepressants at a concentration of no more than 10 microM for 24h. The relative abundance of ADAR2 mRNA to GluR2 pre-mRNA or to beta-actin mRNA was increased after treatment with six of the effective antidepressants, whereas it was unchanged after treatment with milnacipran. Our results suggest that antidepressants have the potency to enhance GluR2 Q/R site-editing by either upregulating the ADAR2 mRNA expression level or other unidentified mechanisms. It may be worth investigating the in vivo efficacy of antidepressants with a specific therapeutic strategy for sporadic ALS in view.

Kallikrein 6 secreted by oligodendrocytes regulates the progression of experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), and experimental autoimmune encephalomyelitis (EAE) is a well‐established animal model of the disease. Here, we examined the pathophysiological role of Kallikrein 6 (Klk6), a serine protease produced by oligodendrocytes (OLs), in EAE using Klk6 knockout (Klk6−/−) mice. Compared with Klk6+/+ (wild‐type) mice, Klk6−/− mice showed milder EAE symptoms, including delayed onset and milder paralysis. Loss of Klk6 suppressed matrix metalloprotease‐9 expression and diminished the infiltration of peripheral inflammatory cells into the CNS by decreasing blood–brain barrier (BBB) permeability and reducing expression levels of inflammatory cytokines, chemokines and their receptors. Scanning electron microscopic analysis revealed demyelination characterized by myelin detachment from the axons in the early phase of EAE progression (days 3–7) in Klk6+/+ mice but not in Klk6−/− mice. Interestingly, anti‐MOG (myelin oligodendrocyte glycoprotein) autoantibody was also detected in the cerebrospinal fluid (CSF) and spinal cord on day 3 after MOG immunization. Furthermore, treatment of primary cultured OLs with anti‐MOG autoantibody induced oligodendroglial morphological changes and increases in myelin basic protein and Klk6 expression. We also developed a novel enzyme‐linked immunoabsorbent assay method for detecting activated KLK6 in human CSF. In human autopsy brain samples, expression of active KLK6 was detected in OLs using an antibody that specifically recognizes the proteins activated form. Taken together, our findings demonstrate that Klk6 secreted by OLs plays a critical role in the pathogenesis of EAE/MS and that it might serve as a potential therapeutic target for MS.

The Frequency and Risk Factors for Ischemic Stroke in Myotonic Dystrophy Type 1 Patients

INTRODUCTION Patients with myotonic dystrophy type 1 have several cardiac abnormalities, especially myocardial conduction disorders. Few studies have investigated cerebral infarction. We investigated the frequency of both symptomatic and asymptomatic ischemic strokes in patients with myotonic dystrophy type 1. METHODS Patients who were diagnosed with myotonic dystrophy type 1 using genetic testing or clinical examinations at Asahikawa Medical Center were included. We retrospectively reviewed their medical history, neuroradiological imaging, electrocardiograms, and treatment. Their CHADS2 and CHA2DS2-VASc scores were calculated. RESULT A total of 108 patients were diagnosed with myotonic dystrophy type 1. Magnetic resonance imaging was performed in 72 and 1 patient whose results were not available was excluded. Among these, 2 patients had atrial flutter and 3 had atrial fibrillation. Regarding the CHADS2 score, 11 patients scored more than 2. Regarding the CHA2DS2-VASc score, 22 patients scored more than 2. Ischemic strokes were found in 9 patients with 1 having an atrial flutter and 4 having atrial fibrillation. All patients with stroke had CHADS2 and CHA2DS2-VASc scores higher than 2. There were significant differences between the 2 groups in atrial fibrillation (P < .001), CHADS2 score (P < .001), and CHA2DS2-VASc score (P < .001). CONCLUSIONS Ischemic stroke in patients with myotonic dystrophy type 1 is associated with atrial fibrillation. The CHADS2 score seems to be useful for the management of patients with myotonic dystrophy type 1. Repeated electrocardiograms are necessary for managing these patients.

Autopsy-proven case of paraneoplastic lower motor neuron disease with sensorimotor neuropathy due to Waldenström's macroglobulinemia: Paraneoplastic motor neuron disease

We report a case of a male patient with a 19‐year history of monoclonal and later polyclonal gammopathy who subsequently developed tetraparesis, bulbar palsy, and respiratory failure. Autopsy findings showed degeneration of the hypoglossal nuclei, prominent neuronal loss and atrophy in the anterior horn of the whole spinal cord despite the presence of mild astrocytosis, degeneration of the gracilis on one side, and infiltration of inflammatory cells, which included B cells and plasma cells in the anterior and posterior roots of the lumbar spinal cord, iliopsoas muscle, and perivascular area of the cervical cord. On immunostaining, cytoplasmic inclusions of phosphorylated transactivation response DNA‐binding protein of 43 kDa were observed in the motor neurons and astrocytes of the hypoglossal nuclei and whole spinal cord. The final diagnosis was paraneoplastic lower motor neuron disease with sensorimotor neuropathy due to Waldenströms macroglobulinemia.