Tau regulates Arc stability in neuronal dendrites via a proteasome-sensitive but ubiquitin-independent pathway

Dina W Yakout; Ankit Shroff; Wei Wei; Vishrut Thaker; Zachary D Allen; Mathew Sajish; Taras Y Nazarko; Angela M Mabb

doi:10.1016/j.jbc.2024.107237

Tau regulates Arc stability in neuronal dendrites via a proteasome-sensitive but ubiquitin-independent pathway

J Biol Chem. 2024 Mar 27;300(5):107237. doi: 10.1016/j.jbc.2024.107237. Online ahead of print.

Authors

Dina W Yakout¹, Ankit Shroff², Wei Wei¹, Vishrut Thaker¹, Zachary D Allen¹, Mathew Sajish³, Taras Y Nazarko², Angela M Mabb⁴

Affiliations

¹ Neuroscience Institute, Georgia State University, Atlanta, Georgia, USA.
² Department of Biology, Georgia State University, Atlanta, Georgia, USA.
³ Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina, USA.
⁴ Neuroscience Institute, Georgia State University, Atlanta, Georgia, USA; Center for Behavioral Neuroscience, Georgia State University, Atlanta, Georgia, USA. Electronic address: amabb@gsu.edu.

PMID: 38552740
DOI: 10.1016/j.jbc.2024.107237

Abstract

Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates of the microtubule-associated protein tau, a main component of neurofibrillary tangles. Alzheimer's disease (AD) is the most common type of tauopathy and dementia, with amyloid-beta pathology as an additional hallmark feature of the disease. Besides its role in stabilizing microtubules, tau is localized at postsynaptic sites and can regulate synaptic plasticity. The activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that plays a key role in synaptic plasticity, learning, and memory. Arc has been implicated in AD pathogenesis and regulates the release of amyloid-beta. We found that decreased Arc levels correlate with AD status and disease severity. Importantly, Arc protein was upregulated in the hippocampus of Tau KO mice and dendrites of Tau KO primary hippocampal neurons. Overexpression of tau decreased Arc stability in an activity-dependent manner, exclusively in neuronal dendrites, which was coupled to an increase in the expression of dendritic and somatic surface GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. The tau-dependent decrease in Arc was found to be proteasome-sensitive, yet independent of Arc ubiquitination and required the endophilin-binding domain of Arc. Importantly, these effects on Arc stability and GluA1 localization were not observed in the commonly studied tau mutant, P301L. These observations provide a potential molecular basis for synaptic dysfunction mediated through the accumulation of tau in dendrites. Our findings confirm that Arc is misregulated in AD and further show a physiological role for tau in regulating Arc stability and AMPA receptor targeting.

Keywords: AMPA receptors; Alzheimer’s disease; arc; proteasome; tau; ubiquitination.