Studies of lissencephaly and neurodegenerative disease reveal novel aspects of cytoplasmic dynein regulation

Kassandra M. Ori-McKenney, Richard Mckenney, Richard B. Vallee

Research output: Chapter in Book/Report/Conference proceedingChapter


The major form of cytoplasmic dynein (dynein 1) is involved in a very wide range of functions. Basic research has revealed much of what is known regarding intra- and extramolecular dynein regulation. This chapter reviews recent clues that have emerged from the investigation of mechanisms underlying cytoplasmic dynein-related diseases. It also discusses the implications of these studies for understanding dynein regulation. It begins with discussing extramolecular regulation of cytoplasmic dynein force generation by LIS1 and NudE/NudEL, which are dynein accessory factors. Mutations in cytoplasmic dynein and dynactin can cause motor neuron disease and sensory neurodegeneration in humans and mice. The study then reasons that identification of the molecular basis for the mutant phenotype helps understand neurodegenerative disease and provides novel insights into cytoplasmic dynein regulation and function. Analysis of lissencephaly and a form of neurodegeneration has provided insight into mechanisms by which dynein motor behavior may be modulated. Evidence indicates that LIS1 affects the dynein powerstroke, identifying a new requirement for external regulatory factors in high-load cytoplasmic dynein functions. Analysis of the Loa mutation has implicated the tail region of the dynein heavy chain in coordination between motor domains. Thus, dynactin and NudE may act in part through the dynein tail, perhaps by upregulating or downregulating an inherent form of tail-mediated motor coordination.

Original languageEnglish (US)
Title of host publicationDyneins
PublisherElsevier Inc.
Number of pages14
ISBN (Print)9780123820044
StatePublished - Dec 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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