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The Journal of Neuroscience, May 6, 2009, 29(18):5758-5767; doi:10.1523/JNEUROSCI.0780-09.2009

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Neurobiology of Disease
Axonal Stress Kinase Activation and Tau Misbehavior Induced by Kinesin-1 Transport Defects

Tomás L. Falzone,^1 * Gorazd B. Stokin,^3 * Concepción Lillo,² Elizabeth M. Rodrigues,¹ Eileen L. Westerman,¹ David S. Williams,² and Lawrence S. B. Goldstein¹

¹Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, and ²Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California 92093, and ³Division of Neurology, University Medical Center and Department of Gerontopsychiatry, University Psychiatric Hospital, SI-1000 Ljubljana, Slovenia

Correspondence should be addressed to Dr. Lawrence S. B. Goldstein, University of California, San Diego, 9500 Gilman Drive, Leichtag Biomedical Research Building, La Jolla, CA 92093-0683. Email: lgoldstein{at}ucsd.edu

Many neurodegenerative diseases exhibit axonal pathology, transport defects, and aberrant phosphorylation and aggregation of the microtubule binding protein tau. While mutant tau protein in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP17) causes aberrant microtubule binding and assembly of tau into filaments, the pathways leading to tau-mediated neurotoxicity in Alzheimer's disease and other neurodegenerative disorders in which tau protein is not genetically modified remain unknown. To test the hypothesis that axonal transport defects alone can cause pathological abnormalities in tau protein and neurodegeneration in the absence of mutant tau or amyloid β deposits, we induced transport defects by deletion of the kinesin light chain 1 (KLC1) subunit of the anterograde motor kinesin-1. We found that upon aging, early selective axonal transport defects in mice lacking the KLC1 protein (KLC1–/–) led to axonopathies with cytoskeletal disorganization and abnormal cargo accumulation. In addition, increased c-jun N-terminal stress kinase activation colocalized with aberrant tau in dystrophic axons. Surprisingly, swollen dystrophic axons exhibited abnormal tau hyperphosphorylation and accumulation. Thus, directly interfering with axonal transport is sufficient to activate stress kinase pathways initiating a biochemical cascade that drives normal tau protein into a pathological state found in a variety of neurodegenerative disorders including Alzheimer's disease.

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Received Feb. 13, 2009; revised March 23, 2009; accepted March 31, 2009.

Correspondence should be addressed to Dr. Lawrence S. B. Goldstein, University of California, San Diego, 9500 Gilman Drive, Leichtag Biomedical Research Building, La Jolla, CA 92093-0683. Email: lgoldstein{at}ucsd.edu

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