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Neurodegeneration mutations in dynactin impair dynein-dependent nuclear migration

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

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 p150glued 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

Topics: Biological Sciences
Publisher: National Academy of Sciences
OAI identifier: oai:pubmedcentral.nih.gov:2664072
Provided by: PubMed Central
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