FUS-linked essential tremor associated with motor dysfunction in Drosophila

Hum Genet. 2016 Nov;135(11):1223-1232. doi: 10.1007/s00439-016-1709-z. Epub 2016 Jul 9.

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.

MeSH terms

  • Amines / metabolism
  • Animals
  • Animals, Genetically Modified
  • Cyclohexanecarboxylic Acids / metabolism
  • Disease Models, Animal
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology
  • Drosophila melanogaster / genetics
  • Essential Tremor / genetics*
  • Essential Tremor / pathology
  • GABAergic Neurons / metabolism
  • GABAergic Neurons / pathology
  • Gabapentin
  • Gene Expression Regulation, Developmental
  • Humans
  • Longevity / genetics*
  • Motor Disorders / genetics*
  • Motor Disorders / pathology
  • Mutation
  • Organ Specificity
  • RNA-Binding Protein FUS / biosynthesis
  • RNA-Binding Protein FUS / genetics*
  • Receptors, GABA / genetics*
  • Receptors, GABA / metabolism
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Serotonergic Neurons / metabolism
  • Serotonergic Neurons / pathology
  • gamma-Aminobutyric Acid / genetics
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Amines
  • Cyclohexanecarboxylic Acids
  • FUS protein, human
  • RNA-Binding Protein FUS
  • Receptors, GABA
  • Receptors, N-Methyl-D-Aspartate
  • gamma-Aminobutyric Acid
  • Gabapentin