Alterations in axonal transport motor proteins in sporadic and experimental Parkinson's disease

Yaping Chu, Gerardo A. Morfini, Lori B. Langhamer, Yinzhen He, Scott T. Brady, Jeffrey H. Kordower

Research output: Contribution to journalArticlepeer-review

178 Scopus citations

Abstract

The progressive loss of the nigrostriatal pathway is a distinguishing feature of Parkinson's disease. As terminal field loss seems to precede cell body loss, we tested whether alterations of axonal transport motor proteins would be early features in Parkinson's disease. There was a decline in axonal transport motor proteins in sporadic Parkinson's disease that preceded other well-known nigral cell-related pathology such as phenotypic downregulation of dopamine. Reductions in conventional kinesin levels precede the alterations in dopaminergic phenotypic markers (tyrosine hydroxylase) in the early stages of Parkinson's disease. This reduction was significantly greater in nigral neurons containing α-synuclein inclusions. Unlike conventional kinesin, reductions in the levels of the cytoplasmic dynein light chain Tctex type 3 subunit were only observed at late Parkinson's disease stages. Reductions in levels of conventional kinesin and cytoplasmic dynein subunits were recapitulated in a rat genetic Parkinson's disease model based on over-expression of human mutant a-synuclein (A30P). Together, our data suggest that α-synuclein aggregation is a key feature associated with reductions of axonal transport motor proteins in Parkinson's disease and support the hypothesis that dopaminergic neurodegeneration following a 'dying-back' pattern involving axonal transport disruption.

Original languageEnglish (US)
Pages (from-to)2058-2073
Number of pages16
JournalBrain
Volume135
Issue number7
DOIs
StatePublished - Jul 2012
Externally publishedYes

Keywords

  • Axonal neuropathies
  • Conventional kinesin
  • Cytoplasmic dynein
  • Parkinson's disease
  • α-synuclein

ASJC Scopus subject areas

  • Clinical Neurology

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