Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway
Open Access
- 21 September 2012
- journal article
- Published by Springer Science and Business Media LLC in Molecular Neurodegeneration
- Vol. 7 (1), 48
- https://doi.org/10.1186/1750-1326-7-48
Abstract
Background Macroautophagy is an evolutionarily conserved mechanism for bulk intracellular degradation of proteins and organelles. Pathological studies have implicated macroautophagy defects in human neurodegenerative disorders of aging including Alzheimer’s disease and tauopathies. Neuronal deficiency of macroautophagy throughout mouse embryonic development results in neurodevelopmental defects and early postnatal mortality. However, the role of macroautophagy in mature CNS neurons, and the relationship with human disease neuropathology, remains unclear. Here we describe mice deficient in an essential macroautophagy component, Atg7, specifically within postnatal CNS neurons. Results Postnatal forebrain-specific Atg7 conditional knockout (cKO) mice displayed age-dependent neurodegeneration and ubiquitin- and p62-positive inclusions. Phosphorylated tau was significantly accumulated in Atg7 cKO brains, but neurofibrillary tangles that typify end-stage human tauopathy were not apparent. A major tau kinase, glycogen synthase kinase 3β (GSK3β), was also accumulated in Atg7 cKO brains. Chronic pharmacological inhibition of tau phosphorylation, or genetic deletion of tau, significantly rescued Atg7-deficiency-mediated neurodegeneration, but did not suppress inclusion formation. Conclusions These data elucidate a role for macroautophagy in the long-term survival and physiological function of adult CNS neurons. Neurodegeneration in the context of macroautophagy deficiency is mediated through a phospho-tau pathway.Keywords
This publication has 62 references indexed in Scilit:
- Wnt Signaling Requires Sequestration of Glycogen Synthase Kinase 3 inside Multivesicular EndosomesCell, 2010
- Autophagy and aging: keeping that old broom workingTrends in Genetics, 2008
- Autophagy fights disease through cellular self-digestionNature, 2008
- Autophagy in the Pathogenesis of DiseaseCell, 2008
- Efficacy of small‐molecule glycogen synthase kinase‐3 inhibitors in the postnatal rat model of tau hyperphosphorylationBritish Journal of Pharmacology, 2007
- Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degenerationProceedings of the National Academy of Sciences of the United States of America, 2007
- Suppression of basal autophagy in neural cells causes neurodegenerative disease in miceNature, 2006
- Loss of autophagy in the central nervous system causes neurodegeneration in miceNature, 2006
- Cell biology of protein misfolding: The examples of Alzheimer's and Parkinson's diseasesNature, 2004
- Protein aggregation and neurodegenerative diseaseNature Medicine, 2004