Skip to main content
Article thumbnail
Location of Repository

Live axonal transport disruption by mutant huntingtin fragments in Drosophila motor neuron axons

By Christopher Sinadinos, T. Burbidge-King, D. Soh, L.M. Thompson, J.L Marsh, Andreas Wyttenbach and Amritpal Mudher

Abstract

Huntington's Disease is a neurodegenerative condition caused by a polyglutamine expansion in the<br/>huntingtin (Htt) protein, which aggregates and also causes neuronal dysfunction. Pathogenic N-terminal htt<br/>fragments perturb axonal transport in vitro. To determine whether this occurs in vivo and to elucidate how<br/>transport is affected, we expressed htt exon 1 with either pathogenic (HttEx1Q93) or non-pathogenic (HttEx1Q20) polyglutamine tracts in Drosophila. We found that HttEx1Q93 expression causes axonal<br/>accumulation of GFP-tagged fast axonal transport vesicles in vivo and leads to aggregates within larval motor<br/>neuron axons. Time-lapse video microscopy, shows that vesicle velocity is unchanged in HttEx1Q93-axons<br/>compared to HttEx1Q20-axons, but vesicle stalling occurs to a greater extent. Whilst HttEx1Q93 expression<br/>did not affect locomotor behaviour, external heat stress unveiled a locomotion deficit in HttEx1Q93 larvae.<br/>Therefore vesicle transport abnormalities amidst axonal htt aggregation places a cumulative burden upon<br/>normal neuronal function under stressful conditions

Year: 2009
OAI identifier: oai:eprints.soton.ac.uk:143775
Provided by: e-Prints Soton

Suggested articles

Citations

  1. (2007). A Drosophila ortholog of the human cylindromatosis tumor suppressor gene regulates triglyceride content and antibacterial defense. doi
  2. (2009). Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. doi
  3. (2008). Atrophy and degeneration in sciatic nerve of presymptomatic mice carrying the Huntington's disease mutation. Brain Res. doi
  4. (2003). Axonal transport of membranous and nonmembranous cargoes: a unified perspective. doi
  5. (1999). Axonal transport of N-terminal huntingtin suggests early pathology of corticostriatal projections in Huntington disease. doi
  6. (2001). Centrosome disorganization in fibroblast cultures derived from R6/2 Huntington's disease (HD) transgenic mice and HD patients. doi
  7. (2004). Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington's disease. doi
  8. (2000). Delaying the onset of Huntington's in mice. doi
  9. (1988). Differential loss of striatal projection neurons in Huntington disease. doi
  10. (2003). Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. doi
  11. Exon 1 of the HD genewith an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. doi
  12. (2004). GSK-3beta inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila. doi
  13. (2001). Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. doi
  14. (2001). Huntingtin aggregate-associated axonal degeneration is an early pathological event in Huntington's disease mice.
  15. (2003). Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity. doi
  16. (2006). JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transport. doi
  17. (1996). Kinesin mutations cause motor neuron disease phenotypes by disrupting fast axonal transport in Drosophila.
  18. (2004). Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. doi
  19. (2008). N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking. doi
  20. (2003). Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport. doi
  21. (2005). Polyglutamine diseases and transport problems: deadly traffic jams on neuronal highways. doi
  22. (1992). Preferential loss of striato-external pallidal projection neurons in presymptomatic Huntington's disease. doi
  23. (2006). Progressive disruption of cellular protein folding in models of polyglutamine diseases. doi
  24. (2006). Reversible disruption of dynactin 1-mediated retrograde axonal transport in polyglutamine-induced motor neuron degeneration. doi
  25. (1990). Storage and fast transport of noradrenaline, dopamine beta-hydroxylase and neuropeptide Y in dog sciatic nerve axons. doi
  26. (2005). Suppression of Huntington's disease pathology in Drosophila by human single-chain Fv antibodies. doi
  27. (2008). Suppression of neurodegeneration and increased neurotransmission caused by expanded full-length huntingtin accumulating in the cytoplasm. doi
  28. (1993). Targeted gene expression as a means of altering cell fates and generating dominant phenotypes.
  29. The Huntington's Disease Collaborative Research Group,1993. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. doi
  30. (1999). Ultrastructural localization and progressive formation of neuropil aggregates in Huntington's disease transgenic mice. doi
  31. (2004). Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease ageof onset. doi

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.