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Kinesin-1 transport reductions enhance human tau hyperphosphorylation aggregation and neurodegeneration in animal models of tauopathies

Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Human Molecular Genetics (Impact Factor: 6.68). 11/2010; 19(22):4399-408. DOI: 10.1093/hmg/ddq363
Source: PubMed

ABSTRACT Neurodegeneration induced by abnormal hyperphosphorylation and aggregation of the microtubule-associated protein tau defines neurodegenerative tauopathies. Destabilization of microtubules by loss of tau function and filament formation by toxic gain of function are two mechanisms suggested for how abnormal tau triggers neuronal loss. Recent experiments in kinesin-1 deficient mice suggested that axonal transport defects can initiate biochemical changes that induce activation of axonal stress kinase pathways leading to abnormal tau hyperphosphorylation. Here we show using Drosophila and mouse models of tauopathies that reductions in axonal transport can exacerbate human tau protein hyperphosphorylation, formation of insoluble aggregates and tau-dependent neurodegeneration. Together with previous work, our results suggest that non-lethal reductions in axonal transport, and perhaps other types of minor axonal stress, are sufficient to induce and/or accelerate abnormal tau behavior characteristic of Alzheimer's disease and other neurodegenerative tauopathies.

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Available from: Tomas Falzone, Jul 11, 2014
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    • "In contrast, elevated phosphorylation of tau results in an increased overall slow rate of tau transport in neurons, and inhibiting GSK-3 phosphorylation of tau reduces its motility (Cuchillo-Ibanez et al., 2008). Defective axonal transport has been suggested to underlie some forms of neurodegenerative disease (De Vos et al., 2008; Falzone et al., 2010), although the mechanisms responsible are not established. Because, in addition to affecting its transport, tau phosphorylation affects its ability to be degraded (Ding et al., 2006; Johnson, 2006), we examined the contributions of the ubiquitin-proteasome system (UPS) and of macroautophagy (autophagy) to tau degradation in the context of tau transport. "
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    • "Although it is impossible to definitively exclude the possibility of off-target effects of EpoD that might lead to increased degradation of misfolded tau, it is interesting to note that kinesin-1 deficient mice develop dystrophic axons with increased amounts of hyperphosphorylated tau (Falzone et al., 2009). Moreover, JNPL3 tau Tg mice crossed to kinesin light chain knockout mice have an exacerbation of tau pathology (Falzone et al., 2010). Thus, it appears that impaired FAT can lead to an enhancement of tau pathology, perhaps through JNK pathway activation (Falzone et al., 2009). "
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