γ-diketone axonopathy: Analyses of cytoskeletal motors and highways in CNS myelinated axons

Lihai Zhang, Terrence Gavin, Anthony P. DeCaprio, Richard M. LoPachin

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

2,5-Hexanedione (HD) intoxication is associated with axon atrophy that might be responsible for the characteristic gait abnormalities, hindlimb skeletal muscle weakness and other neurological deficits that accompany neurotoxicity. Although previous mechanistic research focused on neurofilament triplet proteins (NFL, NFM, NFH), other cytoskeletal targets are possible. Therefore, to identify potential non-NF protein targets, we characterized the effects of HD on protein-protein interactions in cosedimentation assays using microtubules and NFs prepared from spinal cord of rats intoxicated at different daily dose rates (175 and 400 mg/kg/day). Results indicate that HD did not alter the presence of α -or β-tubulins in these preparations, nor were changes noted in the distribution of either anterograde (KIF1A, KIF3, KIF5) or retrograde (dynein) molecular motors. The cosedimentation of dynactin, a dynein-associated protein, also was not affected. Immunoblot analysis of microtubule-associated proteins (MAPs) in microtubule preparations revealed substantial reductions (45-80%) in MAP1A, MAP1B heavy chain, MAP2, and tau regardless of HD dose rate. MAP1B light chain content was not altered. Finally, HD intoxication did not influence native NF protein content in either preparation. As per previous research, microtubule and NF preparations were enriched in high-molecular weight NF species. However, these NF derivatives were common to both HD and control samples, suggesting a lack of pathognomonic relevance. These data indicate that, although motor proteins were not affected, HD selectively impaired MAPmicrotubule binding, presumably through adduction of lysine residues that mediate such interactions. Given their critical role in cytoskeletal physiology, MAPs could represent a relevant target for the induction of γ-diketone axonopathy.

Original languageEnglish (US)
Pages (from-to)180-189
Number of pages10
JournalToxicological Sciences
Volume117
Issue number1
DOIs
StatePublished - Jun 16 2010

Keywords

  • Axon atrophy
  • Axonal cytoskeleton
  • Microtubule-associated proteins
  • Neurofilament
  • Protein adduct
  • γ-diketone neuropathy

ASJC Scopus subject areas

  • Toxicology

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