Neurodegeneration mutations in dynactin impair dynein-dependent nuclear migration

Jeffrey K. Moore, David Sept, John A. Cooper

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Neurodegenerative disease in humans and mice can be caused by mutations affecting the microtubule motor dynein or its biochemical regulator, dynactin, a multiprotein complex required for dynein function (1-4). A single amino acid change, G59S, in the conserved cytoskeletal-associated protein glycine-rich (CAP-Gly) domain of the p150 glued subunit of dynactin can cause motor neuron degeneration in humans and mice, which resembles ALS (2, 5-8). The molecular mechanism by which G59S impairs the function of dynein is not understood. Also, the relevance of the CAP-Gly domain for dynein motility has not been demonstrated in vivo. Here, we generate a mutant that is analogous to G59S in budding yeast, and show that this mutation produces a highly specific phenotype related to dynein function. The effect of the point mutation is identical to that of complete loss of the CAP-Gly domain. Our results demonstrate that the CAP-Gly domain has a critical role in the initiation and persistence of dynein-dependent movement of the mitotic spindle and nucleus, but it is otherwise dispensable for dynein-based movement. The need for this function appears to be context-dependent, and we speculate that CAP-Gly activity may only be necessary when dynein needs to overcome high force thresholds to produce movement.

Original languageEnglish
Pages (from-to)5147-5152
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number13
DOIs
StatePublished - Mar 31 2009

Keywords

  • Cell division
  • Microtubules
  • Motility
  • Nucleus

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