Microtubule transport defects in neurological and ciliary disease

McKusick-Nathans Institute of Genetic Medicine, John Hopkins University, 533 Broadway Research Building, 733 N. Broadway, Baltimore, Maryland 21205, USA.
Cellular and Molecular Life Sciences CMLS (Impact Factor: 5.81). 08/2005; 62(14):1556-70. DOI: 10.1007/s00018-005-5007-5
Source: PubMed


Microtubules are primarily responsible for facilitating long-distance transport of both proteins and organelles. Given the critical role of this process in cellular function, it is not surprising that perturbation of microtubule-based transport can lead to diverse phenotypes in humans, including cancer and neurodegenerative disorders such as Alzheimer or Huntington disease. Recent investigations have also indicated that defects in specialized microtubule-based transport systems, such as mutations affecting the transport of protein particles along the length of cilia (intraflagellar transport) can cause retinal dystrophy, polycystic kidney disease or more complex syndromic phenotypes, such as Bardet-Biedl syndrome. In this review, we discuss recent findings implicating defects in microtubule-associated transport and motor proteins in a variety of diseases, particularly the role of defective microtubular transport in neurological and ciliary disease. These defects frequently display phenotypic consequences that manifest as human disease yet do not cause organismal lethality.

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    • "Its many functions include transporting and positioning diverse cargos (e.g., mRNAs, proteins, and organelles) during interphase, exerting tension between the microtubule network and cell cortex during cell migration, and helping to construct the spindle during mitosis and meiosis (Karki and Holzbaur, 1999; Vale, 2003). Regulation of dynein is therefore critical, and human diseases arise from its dysfunction (Gerdes and Katsanis, 2005). In addition to task-specific regulators, cytoplasmic dynein has three ubiquitous cofactors that are required for most, if not all, of its functions across eukaryotes (Kardon and Vale, 2009; Vallee et al., 2012): the dynactin complex and two proteins analyzed in this study, Lis1 and Nudel. "
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    ABSTRACT: The lissencephaly protein Lis1 has been reported to regulate the mechanical behavior of cytoplasmic dynein, the primary minus-end-directed microtubule motor. However, the regulatory mechanism remains poorly understood. Here, we address this issue using purified proteins from Saccharomyces cerevisiae and a combination of techniques, including single-molecule imaging and single-particle electron microscopy. We show that rather than binding to the main ATPase site within dynein's AAA+ ring or its microtubule-binding stalk directly, Lis1 engages the interface between these elements. Lis1 causes individual dynein motors to remain attached to microtubules for extended periods, even during cycles of ATP hydrolysis that would canonically induce detachment. Thus, Lis1 operates like a "clutch" that prevents dynein's ATPase domain from transmitting a detachment signal to its track-binding domain. We discuss how these findings provide a conserved mechanism for dynein functions in living cells that require prolonged microtubule attachments.
    Cell 08/2012; 150(5):975-86. DOI:10.1016/j.cell.2012.07.022 · 32.24 Impact Factor
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    • "Suppression of microtubule dynamics by microtubule-targeting drugs, such as the vinca alkaloids and taxol, can engage the mitotic spindle checkpoint, arresting the cell cycle progression at mitosis and eventually leading to apoptosis (Jordan and Wilson, 2004). However , direct inhibition of microtubule dynamics may disrupt a number of cellular processes including the transport of intracellular cargo or organelles across long distances (Gerdes and Katsanis, 2005b). Concerted efforts are ongoing to identify, design, and develop antimitotic agents that bind indirectly to tubulin and alter microtubule dynamics, but with minimal toxicity to normal tissues. "
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    • "They extend from, and are continuous with, the cell membrane. Ciliary proteins are synthesized in the cell body and transported to the tip of the ciliary axoneme by intraflagellar transport (IFT), a highly regulated anterograde and retrograde translocation of polypeptide complexes along the length of the axoneme (Badano et al., 2005; Gerdes and Katsanis, 2005). "
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