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Axonal stress kinase activation and tau misbehavior induced by kinesin-1 transport defectsFalzone, Tomás L. ...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 pathologicalabnormalities in tau protein and neurodegeneration in the absence of mutant tau or amyloid beta 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 interferingwith 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.Source: The Journal of neuroscience. - ISSN 0270-6474 (Letn. 29, št. 18, 2009, str. 5758-5767)Type of material - article, component partPublish date - 2009Language - englishCOBISS.SI-ID - 27161817
Author
Falzone, Tomás L. |
Stokin, Gorazd Bernard |
Lillo, Conceptión |
Rodrigues, Elizabeth M.
Topics
Age Factors |
Amyloid Beta-Protein Precursor |
Genetics |
Metabolism |
Animals |
Animals, Newborn |
Axons |
Metabolism |
Ultrastructure |
Cells, Cultured |
Cytoskeleton |
Metabolism |
Ultrastructure |
Hippocampus |
Cytology |
Kymography |
Methods |
Luminescent Proteins |
Genetics |
Mice |
Mice, Inbred C57bl |
Mice, Knockout |
Microscopy, Electron, Scanning |
Methods |
Microtubule-Associated Proteins |
Deficiency |
Metabolism |
Nerve Tissue Proteins |
Metabolism |
Neurofilament Proteins |
Metabolism |
Neurons |
Cytology |
Ultrastructure |
Organelles |
Metabolism |
Ultrastructure |
Statistics, Nonparametric |
Transfection |
Methods |
Tau Proteins |
Genetics |
Metabolism |
Živali novorojene |
Organele |
Statistika neparametrična |
Nevrofilamentne beljakovine |
Živali |
Mikroizvodila-povezane beljakovine |
Nevroni |
Citoskelet |
Luminiscentne beljakovine |
Miši |
Miši seva C57BL |
Tau beljakovine |
Aksoni |
Mikroskopija elektronska, vrstična |
Starostni faktorji |
Kimografija |
Celične kulture |
Hipokampus |
Miši Knockout |
Živčno tkivo, beljakovine |
Amiloidna beta-beljakovinska predstopnja |
Transfekcija
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Falzone, Tomás L. | ![]() |
Stokin, Gorazd Bernard | 16418 |
Lillo, Conceptión | ![]() |
Rodrigues, Elizabeth M. | ![]() |
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