Abstract
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.
Highlights
Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies
We propose that the toxic effect of acetylated tau on chaperone-mediated autophagy (CMA) described in this study could be responsible for the CMA dysfunctions observed in brains from Alzheimer’s disease (AD) patients and contribute to disease propagation, as demonstrated here in a mouse model of tauopathy
As previously described in cultured cells[32], we found that part of cellular tau was degraded in lysosomes, but that inhibition of macroautophagy with the PI3Kinase inhibitor 3methyladenine (3MA) only prevented degradation of a fraction of tau protein (Fig. 1a)
Summary
Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. We observed an increase in macroautophagy activity in cultured cells upon expression of the acetylation-mimetic form of tau (Supplemental Fig. 1h).
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