Yukie Kushimura

An Adult Case of Anti-Myelin Oligodendrocyte Glycoprotein (MOG) Antibody-associated Multiphasic Acute Disseminated Encephalomyelitis at 33-year Intervals

Acute disseminated encephalomyelitis (ADEM) followed by optic neuritis (ON) has been reported as a distinct phenotype associated with anti-myelin oligodendrocyte protein (MOG) antibody. We herein report the case of a 37-year-old woman who was diagnosed with ADEM at 4 years old of age and who subsequently developed ON followed by recurrent ADEM 33 years after the initial onset. A serum analysis showed anti-MOG antibody positivity. This phenotype has only previously been reported in pediatric cases. Neurologists thus need to be aware that the phenotype may occur in adult patients, in whom it may be assumed to be atypical multiple sclerosis.

NPM-hMLF1 fusion protein suppresses defects of a Drosophila FTLD model expressing the human FUS gene

Fused in sarcoma (FUS) was identified as a component of typical inclusions in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). In FTLD, both nuclear and cytoplasmic inclusions with wild-type FUS exist, while cytoplasmic inclusions with a mutant-form of FUS occur in many ALS cases. These observations imply that FUS plays a role across these two diseases. In this study, we examined the effect of several proteins including molecular chaperons on the aberrant eye morphology phenotype induced by overexpression of wild-type human FUS (hFUS) in Drosophila eye imaginal discs. By screening, we found that the co-expression of nucleophosmin–human myeloid leukemia factor 1 (NPM-hMLF1) fusion protein could suppress the aberrant eye morphology phenotype induced by hFUS. The driving of hFUS expression at 28 °C down-regulated levels of hFUS and endogenous cabeza, a Drosophila homolog of hFUS. The down-regulation was mediated by proteasome dependent degradation. Co-expression of NPM-hMLF1 suppressed this down-regulation. In addition, co-expression of NPM-hMLF1 partially rescued pharate adult lethal phenotype induced by hFUS in motor neurons. These findings with a Drosophila model that mimics FTLD provide clues for the development of novel FTLD therapies.

Genetic screening of the genes interacting with Drosophila FIG4 identified a novel link between CMT-causing gene and long noncoding RNAs

ABSTRACT Neuron‐specific knockdown of the dFIG4 gene, a Drosophila homologue of human FIG4 and one of the causative genes for Charcot‐Marie‐Tooth disease (CMT), reduces the locomotive abilities of adult flies, as well as causing defects at neuromuscular junctions, such as reduced synaptic branch length in presynaptic terminals of the motor neurons in third instar larvae. Eye imaginal disc‐specific knockdown of dFIG4 induces abnormal morphology of the adult compound eye, the rough eye phenotype. In this study, we carried out modifier screening of the dFIG4 knockdown‐induced rough eye phenotype using a set of chromosomal deficiency lines on the second chromosome. By genetic screening, we detected 9 and 15 chromosomal regions whose deletions either suppressed or enhanced the rough eye phenotype induced by the dFIG4 knockdown. By further genetic screening with mutants of individual genes in one of these chromosomal regions, we identified the gene CR18854 that suppressed the rough eye phenotype and the loss‐of‐cone cell phenotype. The CR18854 gene encodes a long non‐coding RNA (lncRNA) consisting of 2566 bases. Mutation and knockdown of CR18854 patially suppressed the enlarged lysosome phenotype induced by Fat body‐specific knockdown of dFIG4. Further characterization of CR18854, and a few other lncRNAs in relation to dFIG4 in neuron, using neuron‐specific dFIG4 knockdown flies indicated a genetic link between the dFIG4 gene and lncRNAs including CR18854 and hsr&ohgr;. We also obtained data indicating genetic interaction between CR18854 and Cabeza, a Drosophila homologue of human FUS, which is one of the causing genes for amyotrophic lateral sclerosis (ALS). These results suggest that lncRNAs such as CR18854 and hsr&ohgr; are involved in a common pathway in CMT and ALS pathogenesis. HIGHLIGHTSThe dFIG4 gene, a Drosophila homologue of human FIG4 is a causing genes for Charcot‐Marie‐Tooth disease.The CR18854 gene encoding a long hairpin RNA was identified as a genetic interactant with dFIG4.The other long non‐coding RNA hsr&ohgr; also genetically interacts with dsss4.The CR18854 gene genetically interacts with Drosophila FUS (Cabeza), a causing gene for ALS.The lncRNAs such as CR18854 and hsr&ohgr; may involve in common pathway for CMT and ALS pathogenesis.

Hippo, Drosophila MST, is a novel modifier of motor neuron degeneration induced by knockdown of Caz, Drosophila FUS

Abstract Mutations in the Fused in Sarcoma (FUS) gene have been identified in familial ALS in human. Drosophila contains a single ortholog of human FUS called Cabeza (Caz). We previously established Drosophila models of ALS targeted to Caz, which developed the locomotive dysfunction and caused anatomical defects in presynaptic terminals of motoneurons. Accumulating evidence suggests that ALS and cancer share defects in many cellular processes. The Hippo pathway was originally discovered in Drosophila and plays a role as a tumor suppressor in mammals. We aimed to determine whether Hippo pathway genes modify the ALS phenotype using Caz knockdown flies. We found a genetic link between Caz and Hippo (hpo), the Drosophila ortholog of human Mammalian sterile 20‐like kinase (MST) 1 and 2. Loss‐of‐function mutations of hpo rescued Caz knockdown‐induced eye‐ and neuron‐specific defects. The decreased Caz levels in nuclei induced by Caz knockdown were also rescued by loss of function mutations of hpo. Moreover, hpo mRNA level was dramatically increased in Caz knockdown larvae, indicating that Caz negatively regulated hpo. Our results demonstrate that hpo, Drosophila MST, is a novel modifier of Drosophila FUS. Therapeutic targets that inhibit the function of MST could modify the pathogenic processes of ALS. HighlightsMutation in Hippo suppressed aberrant eye morphology induced by Cabeza knockdown.Mutation in Hippo suppressed neuron‐specific defects induced by Cabeza knockdown.Mutation in Hippo restored Cabeza protein in the nucleus.Hippo mRNA level increased in Cabeza knockdown.Cabeza may negatively regulate hippo.