Disruption of Axonal Transport by Loss of Huntingtin or Expression of Pathogenic PolyQ Proteins in Drosophila

Gunawardena, Shermali; Her, Lu-Shiun; Brusch, Richard G.; Laymon, Robert A.; Niesman, Ingrid R.; Gordesky-Gold, Beth; Sintasath, Louis; Bonini, Nancy M.; Goldstein, Lawrence S.B.

doi:10.1016/s0896-6273(03)00594-4

Cited by 587 publications

(512 citation statements)

References 50 publications

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“…Consistent with our hypothesis that Htt-Q128 expression causes neurodegeneration secondary to impairment of axonal transport, recent studies have found that neurodegeneration is a primary consequence of axonal transport defects in non-polyQ diseases as well, including Alzheimer's disease (26)(27)(28). During review of our manuscript, two reports have been published that document similar axonal transport defects in HD models (29,30). Determining the precise mechanisms by which Htt aggregates physically attach to the axonal cytoskeleton will likely provide important insights into the mechanisms of axonal transport blockage in HD.…”

Section: Resultssupporting

confidence: 87%

Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington's disease

Lee

Yoshihara

Littleton

2004

Proc. Natl. Acad. Sci. U.S.A.

313

238

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Huntington's disease is an autosomal dominant neurodegenerative disorder caused by expansion of a polyglutamine tract in the huntingtin protein that results in intracellular aggregate formation and neurodegeneration. Pathways leading from polyglutamine tract expansion to disease pathogenesis remain obscure. To elucidate how polyglutamine expansion causes neuronal dysfunction, we generated Drosophila transgenic strains expressing human huntingtin cDNAs encoding pathogenic (Htt-Q128) or nonpathogenic proteins (Htt-Q0). Whereas expression of Htt-Q0 has no discernible effect on behavior, lifespan, or neuronal morphology, pan-neuronal expression of Htt-Q128 leads to progressive loss of motor coordination, decreased lifespan, and time-dependent formation of huntingtin aggregates specifically in the cytoplasm and neurites. Huntingtin aggregates sequester other expanded polyglutamine proteins in the cytoplasm and lead to disruption of axonal transport and accumulation of aggregates at synapses. In contrast, Drosophila expressing an expanded polyglutamine tract alone, or an expanded polyglutamine tract in the context of the spinocerebellar ataxia type 3 protein, display only nuclear aggregates and do not disrupt axonal trafficking. Our findings indicate that nonnuclear events induced by cytoplasmic huntingtin aggregation play a central role in the progressive neurodegeneration observed in Huntington's disease.

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Section: Resultssupporting

confidence: 87%

Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington's disease

Lee

Yoshihara

Littleton

2004

Proc. Natl. Acad. Sci. U.S.A.

313

238

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“…One strong possibility is axonal transport. Disruption of axonal transport can lead to neuronal cell death in mice (LaMonte et al, 2002) and Drosophila (Gunawardena and Goldstein, 2001;Gunawardena et al, 2003). Although the underlying mechanism connecting microtubule dynamics to axonal transport is unclear, low concentrations of taxol have been shown to compromise axonal transport (Nakata and Hirokawa, 2003).…”

Section: How Might Tau Dysfunction Cause Neurodegeneration?mentioning

confidence: 99%

Modulation of Microtubule Dynamics by Tau in Living Cells: Implications for Development and Neurodegeneration

Bunker

Wilson

Jordan

et al. 2004

MBoC

134

127

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The neural microtubule-associated protein tau binds to and stabilizes microtubules. Because of alternative mRNA splicing, tau is expressed with either 3 or 4 C-terminal repeats. Two observations indicate that differences between these tau isoforms are functionally important. First, the pattern of tau isoform expression is tightly regulated during development. Second, mutation-induced changes in tau RNA splicing cause neuronal cell death and dementia simply by altering the isoform expression ratio. To investigate whether 3-and 4-repeat tau differentially regulate microtubule behavior in cells, we microinjected physiological levels of these two isoforms into EGFP-tubulin-expressing cultured MCF7 cells and measured the effects on the dynamic instability behavior of individual microtubules by time-lapse microscopy. Both isoforms suppressed microtubule dynamics, though to different extents. Specifically, 4-repeat tau reduced the rate and extent of both growing and shortening events. In contrast, 3-repeat tau stabilized most dynamic parameters about threefold less potently than 4-repeat tau and had only a minimal ability to suppress shortening events. These differences provide a mechanistic rationale for the developmental shift in tau isoform expression and are consistent with a loss-of-function model in which abnormal tau isoform expression results in the inability to properly regulate microtubule dynamics, leading to neuronal cell death and dementia. INTRODUCTIONThe microtubule-associated protein tau promotes neuronal cell polarization and axonal outgrowth; it is also necessary for maintaining axonal morphology and axonal transport (Caceres and Kosik, 1990;Esmaeli-Azad et al., 1994;Trinczek et al., 1999;Stamer et al., 2002). Alternatively, abnormal tau is the major component of neurofibrillary tangles, hallmark pathological features of Alzheimer's disease and related dementias.Mechanistically, tau acts by binding to microtubules directly and regulating their growing, shortening, and treadmilling dynamics (Drechsel et al., 1992;Panda et al., 1995Panda et al., , 1999Trinczek et al., 1995). Because tight regulation of microtubule dynamics and microtubule behavior can be critical to cell viability (Jordan et al., 1996;Goncalves et al., 2001), fine regulation of tau activity may be equally critical.Tau activity is regulated in part by alternative mRNA splicing, which leads to the expression of two families of tau isoforms, those containing four C-terminal repeats and those with three such repeats ( Figure 1A; Lee et al., 1988;Himmler, 1989). In vitro studies have shown that 4-repeat tau binds to, assembles, and stabilizes microtubules more effectively than 3-repeat tau (Butner and Kirschner, 1991;Gustke et al., 1994;Trinczek et al., 1995;Goode et al., 2000;Panda et al., 2003). However, there are limited data assessing the abilities of 3-or 4-repeat tau to modulate dynamics in a complex cellular environment.The importance of functional differences between 3-and 4-repeat tau is highlighted by two observations. First, altho...

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“…Polyglutamine expansion in mutant Htt causes Huntington's disease, a neurodegenerative disorder that primarily affects striatal neurons. Mutant Htt disrupts axonal transport in squid axoplasm (7), Drosophila (8), and mammals (9,10), suggesting a role for the protein in vesicle transport. Htt interacts with various proteins implicated in trafficking (6,11), including Htt-associated protein-1 (HAP1), which in turn interacts with both dynactin and kinesin (12)(13)(14).…”

mentioning

confidence: 99%

Huntingtin facilitates dynein/dynactin-mediated vesicle transport

Caviston

Ross²,

Antony³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

264

216

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Disruption of Axonal Transport by Loss of Huntingtin or Expression of Pathogenic PolyQ Proteins in Drosophila

Cited by 587 publications

References 50 publications

Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington's disease

Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington's disease

Modulation of Microtubule Dynamics by Tau in Living Cells: Implications for Development and Neurodegeneration

Huntingtin facilitates dynein/dynactin-mediated vesicle transport

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