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Serum tyrosine and phenylalanine levels increase during aging and age-associated disorders. We previously showed that tyrosyl-tRNA synthetase (TyrRS/YARS1) is reduced in Alzheimer's Disease (AD) brains, and tyrosine and phenylalanine decrease TyrRS in neurons. Here, we found that tau is a negative regulator, whereas estrogen and leucine act as positive regulators of TyrRS. Young female mice exhibit increased TyrRS in the cortex compared to male mice. Notably, young Tau knockout male, but not female mice showed increased cortical TyrRS. Tau accumulation in middle-aged female mice did not decrease cortical TyrRS compared to males, suggesting that middle aged females are resilient to tau-mediated TyrRS depletion. Tyrosine and phenylalanine treatment decreased tubulin tyrosination, activated DNA repair pathways, and protected against etoposide (ETO) and camptothecin (CPT)-induced toxicity, respectively, in neurons. While tyrosine facilitated topoisomerase 1 (TOP1) recruitment to chromatin and inhibited global transcription, in contrast, phenylalanine recruited topoisomerase 2 beta (TOP2β) to chromatin and stimulated global transcription. Furthermore, tyrosine decreased the presence of DNA fragments in a comet assay whereas phenylalanine increased them. Addition of cis-resveratrol (cis-RSV) protected against tyrosine-induced transcription inhibition by facilitating the recruitment of both TOP1 and TOP2β to chromatin and increasing tubulin tyrosination. Moreover, cis-RSV decreased both total and phosphorylated tau and protected neurons against amyloid beta (Aβ)-induced neurite degeneration and DNA damage. Gene expression profiling using human embryonic stem cell (hESC)-derived neurons demonstrated that cis-RSV is a broad-spectrum neuroprotective and anti-viral agent. In contrast, trans-RSV mimics phenylalanine-induced gene expression, including downregulation of long genes and induction of an AD-like gene expression signature. This work suggests that age and disease-associated increases in serum tyrosine and phenylalanine levels would activate neuronal DNA repair while inhibiting transcription and tubulin tyrosination. cis-RSV protects against their toxicity by restoring tubulin tyrosination, TOP1 and TOP2β-mediated transcription, and decreasing tau in primary neurons. 

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. 

Synaptic plasticity relies on rapid, yet spatially precise signaling to alter synaptic strength. Arc is a brain enriched protein that is rapidly expressed during learning-related behaviors and is essential for regulating metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD). We previously showed that disrupting the ubiquitination capacity of Arc enhances mGluR-LTD; however, the consequences of Arc ubiquitination on other mGluR-mediated signaling events is poorly characterized. Here we find that pharmacological activation of Group I mGluRs with S-3,5-dihydroxyphenylglycine (DHPG) increases Ca²⁺release from the endoplasmic reticulum (ER). Disrupting Arc ubiquitination on key amino acid residues enhances DHPG-induced ER-mediated Ca²⁺release. These alterations were observed in all neuronal subregions except secondary branchpoints. Deficits in Arc ubiquitination altered Arc self-assembly and enhanced its interaction with calcium/calmodulin-dependent protein kinase IIb (CaMKIIb) and constitutively active forms of CaMKII in HEK293 cells. Colocalization of Arc and CaMKII was altered in cultured hippocampal neurons, with the notable exception of secondary branchpoints. Finally, disruptions in Arc ubiquitination were found to increase Arc interaction with the integral ER protein Calnexin. These results suggest a previously unknown role for Arc ubiquitination in the fine tuning of ER-mediated Ca²⁺signaling that may support mGluR-LTD, which in turn, may regulate CaMKII and its interactions with Arc.