Axonal stress kinase activation and tau misbehavior induced by kinesin-1 transport defects

• Autores: Falzone, Tomas Luis; Stokin, Gorazd B.; Lillo, Concepción; Rodrigues, Elizabeth M.; Westerman, Eileen L.; Williams, David S.; Goldstein, Lawrence S. B.
• Año de publicación: 2009
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: AXONAL TRANSPORT; TAU; JNK; ALZHEIMER
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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.
Fil: Falzone, Tomas Luis. Howard Hughes Medical Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Stokin, Gorazd B.. University Psychiatric Hospital; Eslovenia
Fil: Lillo, Concepción. University of California at San Diego; Estados Unidos
Fil: Rodrigues, Elizabeth M.. Howard Hughes Medical Institute; Estados Unidos
Fil: Westerman, Eileen L.. Howard Hughes Medical Institute; Estados Unidos
Fil: Williams, David S.. University of California at San Diego; Estados Unidos
Fil: Goldstein, Lawrence S. B.. Howard Hughes Medical Institute; Estados Unidos