title: FUS-linked essential tremor associated with motor dysfunction in Drosophila.
abstract: Essential tremor (ET) is one of the most common adult-onset neurological disorders which produce motor and non-motor symptoms. To date, there are no gold standard pathological hallmarks of ET, and despite a strong genetic contribution toward ET development, only a few pathogenic mutations have been identified. Recently, a pathogenic FUS-Q290X mutation has been reported in a large ET-affected family; however, the pathophysiologic mechanism underlying FUS-linked ET is unknown. Here, we generated transgenic Drosophila expressing hFUS-WT and hFUS-Q290X and targeted their expression in different tissues. We found that the targeted expression of hFUS-Q290X in the dopaminergic and the serotonergic neurons did not cause obvious neuronal degeneration, but it resulted in motor dysfunction which was accompanied by impairment in the GABAergic pathway. The involvement of the GABAergic pathway was supported by rescue of motor symptoms with gabapentin. Interestingly, we observed gender specific downregulation of GABA-R and NMDA-R expression and reduction in serotonin level. Overexpression of hFUS-Q290X also caused an increase in longevity and this was accompanied by downregulation of the IIS/TOR signalling pathway. Our in vivo studies of the hFUS-Q290X mutation in Drosophila link motor dysfunction to impairment in the GABAergic pathway. Our findings would facilitate further efforts in unravelling the pathophysiology of ET.
authors.affiliation: National Neuroscience Institute, 20 College Road, The Academia, Level 9 (Discovery Tower), Singapore, 169856, Singapore. murni.tio@singhealth.com.sg.
authors.forename: Murni
authors.initials: M
authors.lastname: Tio
authors.affiliation: National Neuroscience Institute, 20 College Road, The Academia, Level 9 (Discovery Tower), Singapore, 169856, Singapore.
authors.forename: Rujing
authors.initials: R
authors.lastname: Wen
authors.affiliation: National Neuroscience Institute, 20 College Road, The Academia, Level 9 (Discovery Tower), Singapore, 169856, Singapore.
authors.forename: Yih Lin
authors.initials: YL
authors.lastname: Lim
authors.affiliation: National Neuroscience Institute, 20 College Road, The Academia, Level 9 (Discovery Tower), Singapore, 169856, Singapore.
authors.forename: Huashan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Yong Loo Lin School of Medicine, National University of Singapore, 12 Science Drive 2, Singapore, 117549, Singapore.
authors.forename: Shuo-Chien
authors.initials: SC
authors.lastname: Ling
authors.affiliation: Department of Clinical Research, 20 College Road, The Academia, Level 9 (Discovery Tower), Singapore, 169856, Singapore.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: National Neuroscience Institute, 20 College Road, The Academia, Level 9 (Discovery Tower), Singapore, 169856, Singapore. gnrtek@sgh.com.sg.|Department of Clinical Research, 20 College Road, The Academia, Level 9 (Discovery Tower), Singapore, 169856, Singapore. gnrtek@sgh.com.sg.|Department of Neurology, Singapore General Hospital, National Neuroscience Institute, Outram Road, Singapore, 169608, Singapore. gnrtek@sgh.com.sg.|Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singapore. gnrtek@sgh.com.sg.
authors.forename: Eng-King
authors.initials: EK
authors.lastname: Tan
mesh_terms: D000588:Amines / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D003509:Cyclohexanecarboxylic Acids / Q000378:metabolism; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D004331:Drosophila melanogaster / Q000235:genetics; D020329:Essential Tremor / Q000235:genetics* / Q000473:pathology; D059330:GABAergic Neurons / Q000378:metabolism / Q000473:pathology; D000077206:Gabapentin; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008136:Longevity / Q000235:genetics*; D000068079:Motor Disorders / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009928:Organ Specificity; D034702:RNA-Binding Protein FUS / Q000096:biosynthesis / Q000235:genetics*; D018079:Receptors, GABA / Q000235:genetics* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D059326:Serotonergic Neurons / Q000378:metabolism / Q000473:pathology; D005680:gamma-Aminobutyric Acid / Q000235:genetics / Q000378:metabolism
chemical_list: D000588:Amines; D003509:Cyclohexanecarboxylic Acids; C000599550:FUS protein, human; D034702:RNA-Binding Protein FUS; D018079:Receptors, GABA; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin