Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport.
Huntington's and Kennedy's disease are autosomal dominant neurodegenerative diseases caused by pathogenic expansion of polyglutamine tracts. Expansion of glutamine repeats must in some way confer a gain of pathological function that disrupts an essential cellular process and leads to loss of affected neurons. Association of huntingtin with vesicular structures raised the possibility that axonal transport might be altered. Here we show that polypeptides containing expanded polyglutamine tracts, but not normal N-terminal huntingtin or androgen receptor, directly inhibit both fast axonal transport in isolated axoplasm and elongation of neuritic processes in intact cells. Effects were greater with truncated polypeptides and occurred without detectable morphological aggregates.
Szebenyi
Györgyi
G
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Morfini
Gerardo A
GA
Babcock
Alyssa
A
Gould
Milena
M
Selkoe
Kimberly
K
Stenoien
David L
DL
Young
Maureen
M
Faber
Pieter W
PW
MacDonald
Marcy E
ME
McPhaul
Michael J
MJ
Brady
Scott T
ST
D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D048429:Cell Size / Q000502:physiology; D049832:Decapodiformes; D006801:Humans; D000071058:Huntingtin Protein; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics*; D009433:Neural Inhibition / Q000502:physiology; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D010455:Peptides / Q000737:chemistry / Q000235:genetics; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics*; D014407:Tumor Cells, Cultured
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine