Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice
| Autor: | Peter Dongmin Sohn, Bindi Patel, Yves R. Juste, Chao Wang, Alison Goate, Bradley T. Hyman, Mathieu Bourdenx, Celeste M. Karch, Jose A. Rodriguez-Navarro, Susanne Wegmann, Antonio Diaz, Enrique Luengo, Jason E. Gestwicki, Li Gan, Hao Shao, Zapporah T. Young, Ana Maria Cuervo, Manuela G. López, Szu Yu Kuo, Xu Chen, Benjamin Caballero |
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| Rok vydání: | 2021 |
| Předmět: |
pathology [Tauopathies]
0301 basic medicine Male Aging physiopathology [Tauopathies] General Physics and Astronomy Chaperone-Mediated Autophagy Neurodegenerative Inbred C57BL Alzheimer's Disease Mice 0302 clinical medicine Chaperone-mediated autophagy 2.1 Biological and endogenous factors Aetiology Alzheimer's Disease Related Dementias (ADRD) health care economics and organizations Neurons Multidisciplinary Chemistry Neurodegeneration Brain Acetylation Neural ageing humanities Cell biology Frontotemporal Dementia (FTD) Tauopathies metabolism [Neurons] Neurological Female ddc:500 Tauopathy Endosome Science tau Proteins Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Cellular neuroscience mental disorders medicine Acquired Cognitive Impairment Animals Humans Microautophagy Autophagy genetics [Tauopathies] Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) General Chemistry medicine.disease metabolism [tau Proteins] Brain Disorders Mice Inbred C57BL genetics [tau Proteins] 030104 developmental biology metabolism [Brain] Dementia metabolism [Tauopathies] 030217 neurology & neurosurgery |
| Zdroj: | Nature communications, vol 12, iss 1 Nature Communications Nature Communications 12(1), 2238 (2021). doi:10.1038/s41467-021-22501-9 Nature Communications, Vol 12, Iss 1, Pp 1-18 (2021) |
| Popis: | Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release. In fact, experimental blockage of CMA enhances cell-to-cell propagation of pathogenic tau in a mouse model of tauopathy. Furthermore, analysis of lysosomes isolated from brains of patients with tauopathies demonstrates similar molecular mechanisms leading to CMA dysfunction. This study reveals that CMA failure in tauopathy brains alters tau homeostasis and could contribute to aggravate disease progression. The tau protein has been implicated in neurodegenerative disorders and can propagate from cell to cell. Here, the authors show that tau acetylation reduces its degradation by chaperone-mediated autophagy, causing re-routing to other autophagic pathways and increasing extracellular tau release. |
| Databáze: | OpenAIRE |
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