Polyglutamine expansion diseases: failing to deliver

Trends Mol Med. 2005 Feb;11(2):64-70. doi: 10.1016/j.molmed.2004.12.002.


Polyglutamine (polyQ)-expansion diseases are dominantly inherited adult-onset neurodegenerative diseases with unknown pathogenic mechanisms. Current models for pathogenesis include potential toxic effects of polyQ proteins, interference with survival pathways and deregulated gene transcription. Recently, nuclear and aggregate-independent alterations in fast axonal transport (FAT) have been demonstrated for several different polyQ disease models. Given the unique vulnerability of neurons to decrements in FAT, we propose an alternative model for polyQ disease pathogenesis. In this model, FAT is compromised because polyQ proteins affect enzymatic activities involved in FAT regulation. Decrements in FAT ultimately result in a failure to deliver essential cargos to specific neuronal subdomains, including presynaptic terminals, eventually leading to neuronal dysfunction and death. Pharmacological manipulation of such activities might provide the basis for new therapeutic strategies for treating polyQ diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Axonal Transport / physiology*
  • DNA Repeat Expansion
  • Humans
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / metabolism*
  • Neurons / physiology
  • Peptides / genetics*
  • Trinucleotide Repeat Expansion*


  • Peptides
  • polyglutamine