Loss of Spastic Paraplegia Gene Atlastin Induces Age-Dependent Death of Dopaminergic Neurons in Drosophila

Neurobiol Aging. 2008 Jan;29(1):84-94. doi: 10.1016/j.neurobiolaging.2006.09.004. Epub 2006 Oct 9.

Abstract

Hereditary spastic paraplegias (HSPs) are human genetic disorders causing increased stiffness and overactive muscle reflexes in the lower extremities. atlastin (atl) is one of the major genes in which mutations result in HSP. We generated a Drosophila model of HSP that has a null mutation in atl. As they aged, atl null flies were paralyzed by mechanical shock such as bumping or vortexing. Furthermore, the flies showed age-dependent degeneration of dopaminergic neurons. These phenotypes were rescued by targeted expression of atl in dopaminergic neurons or feeding L-DOPA or SK&F 38393, an agonist of dopamine receptor. Our data raised the possibility that one of the causes of HSP disease symptoms in human patients with alt mutations is malfunction or degeneration of dopaminergic neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / administration & dosage
  • Aging*
  • Animals
  • Animals, Genetically Modified
  • Cell Death / genetics
  • Cell Proliferation
  • Dopamine / metabolism*
  • Dopamine Agonists / administration & dosage
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Embryo, Nonmammalian / physiology
  • GTP Phosphohydrolases / deficiency*
  • GTP-Binding Proteins
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics*
  • Green Fluorescent Proteins / genetics
  • Levodopa / administration & dosage
  • Male
  • Membrane Proteins
  • Neurons / drug effects
  • Neurons / pathology*
  • Sequence Alignment / methods
  • Tyrosine 3-Monooxygenase / genetics

Substances

  • Dopamine Agonists
  • Drosophila Proteins
  • Membrane Proteins
  • Green Fluorescent Proteins
  • Levodopa
  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
  • Tyrosine 3-Monooxygenase
  • ATL1 protein, human
  • GTP Phosphohydrolases
  • GTP-Binding Proteins
  • Dopamine