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Tio M.,National Neuroscience Institute | Wen R.,National Neuroscience Institute | Lim Y.L.,National Neuroscience Institute | Wang H.,National Neuroscience Institute | And 6 more authors.
Human Genetics | Year: 2016

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. © 2016 The Author(s)


PubMed | National University of Singapore, National Neuroscience Institute and 20 College Road
Type: Journal Article | Journal: Human genetics | Year: 2016

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.

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