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: 6.39). 11/2010; 19(22):4399-408. DOI: 10.1093/hmg/ddq363
Source: PubMed


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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    • "Decreased KLC1 transport may also stimulate tau hyperphosphorylation and formation of NFTs as well as axonal swellings producing catastrophic damage to axons. Such damage may arise from increased Aβ levels and tau hyperphosphorylation, further disrupting axonal transport [145]. "
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    ABSTRACT: Alzheimer's disease (AD) is one of the most prevalent severe neurological disorders afflicting our aged population. Cognitive decline, a major symptom exhibited by AD patients, is associated with neuritic dystrophy, a degenerative growth state of neurites. The molecular mechanisms governing neuritic dystrophy remain unclear. Mounting evidence indicates that the AD-causative agent, β -amyloid protein (A β ), induces neuritic dystrophy. Indeed, neuritic dystrophy is commonly found decorating A β -rich amyloid plaques (APs) in the AD brain. Furthermore, disruption and degeneration of the neuronal microtubule system in neurons forming dystrophic neurites may occur as a consequence of A β -mediated downstream signaling. This review defines potential molecular pathways, which may be modulated subsequent to A β -dependent interactions with the neuronal membrane as a consequence of increasing amyloid burden in the brain.
    International Journal of Alzheimer's Disease 12/2013; 2013:910502. DOI:10.1155/2013/910502
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    • "Regulation of axonal transport [10,12,19,34,36,71,97,98,105,106,107,108,109,110,111,112,113,114,115,116,117,118]. "
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    ABSTRACT: The hallmarks of neurons are their slender axons which represent the longest cellular processes of animals and which act as the cables that electrically wire the brain, and the brain to the body. Axons extend along reproducible paths during development and regeneration, and they have to be maintained for the life time of an organism. Both axon extension and maintenance essentially depend on the microtubule (MT) cytoskeleton. For this, MTs organise into parallel bundles that are established through extension at the leading axon tips within growth cones, and these bundles then form the architectural backbones, as well as the highways for axonal transport essential for supply and intracellular communication. Axon transport over these enormous distances takes days or even weeks and is a substantial logistic challenge. It is performed by kinesins and dynein / dynactin, which are molecular motors that form close functional links to the MTs they walk along. The intricate machinery which regulates MT dynamics, axonal transport and the motors is essential for nervous system development and function, and its investigation has huge potential to bring urgently required progress in understanding the causes of many developmental and degenerative brain disorders. During the last years new explanations for the highly specific properties of axonal MTs and for their close functional links to motor proteins have emerged, and it has become increasingly clear that motors play active roles also in regulating axonal MT networks. Here, I will provide an overview of these new developments. includes: Table of Drosophila MT motor proteins ( PDF link:
    Neural Development 09/2013; 8:17. DOI:10.1186/1749-8104-8-17 · 3.45 Impact Factor
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    • "Genetic suppression of Miro, an adapter protein essential for mitochondrial axonal transport, exacerbates the neurodegenerative phenotype in Drosophila expressing human tau, through a mechanism dependent upon phosphorylation of tau at S262 by PAR-1, the Drosophila homolog of MARK kinase (105). Similarly, deletion of kinesin light chain-1 results in accumulation of hyperphosphorylated tau and the appearance of axonal spheroids in mice (106), in line with numerous reports that have characterized the binding of tau to kinesin (21, 96–98). "
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    ABSTRACT: Fibrillar deposits of highly phosphorylated tau are a key pathological feature of several neurodegenerative tauopathies including Alzheimer's disease (AD) and some frontotemporal dementias. Increasing evidence suggests that the presence of these end-stage neurofibrillary lesions do not cause neuronal loss, but rather that alterations to soluble tau proteins induce neurodegeneration. In particular, aberrant tau phosphorylation is acknowledged to be a key disease process, influencing tau structure, distribution, and function in neurons. Although typically described as a cytosolic protein that associates with microtubules and regulates axonal transport, several additional functions of tau have recently been demonstrated, including roles in DNA stabilization, and synaptic function. Most recently, studies examining the trans-synaptic spread of tau pathology in disease models have suggested a potential role for extracellular tau in cell signaling pathways intrinsic to neurodegeneration. Here we review the evidence showing that tau phosphorylation plays a key role in neurodegenerative tauopathies. We also comment on the tractability of altering phosphorylation-dependent tau functions for therapeutic intervention in AD and related disorders.
    Frontiers in Neurology 07/2013; 4:83. DOI:10.3389/fneur.2013.00083
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