Chronic over‐expression of ubiquitin impairs learning, reduces synaptic plasticity, and enhances GRIA receptor turnover in mice

Abstract

Ubiquitin is an essential signaling protein that controls many different cellular processes. While cellular ubiquitin levels normally cycle between pools of free and conjugated ubiquitin, the balance of these ubiquitin pools can be shifted by exposure to a variety of cellular stresses. Altered ubiquitin pools are also observed in several neurological disorders, suggesting that imbalances in ubiquitin homeostasis may contribute to neuronal dysfunction. To examine the effects of increased ubiquitin levels on the mammalian nervous system, we generated transgenic mice that express ubiquitin under the control of the Thy1.2 promoter. While we did not detect global changes in levels of ubiquitin conjugates in the hippocampus, we found that increasing ubiquitin levels reduced AMPA (GRIA1-4) receptor expression without affecting the levels of NMDA (GRIN) or GABA A receptors. Ubiquitin over-expression also negatively impacted hippocampus-dependent learning and memory as well as baseline excitability and synaptic plasticity at hippocampal CA3-CA1 synapses. These changes occurred in a dose-dependent manner in that mice with the highest levels of ubiquitin over-expression had the greatest deficits in synaptic function and were the most impaired in the learning and memory tasks. As chronic elevation of ubiquitin expression in neurons is sufficient to cause changes in synaptic function and cognition, altered ubiquitin homeostasis may be an important contributor to the stress-induced changes observed in neurological disorders.

A negative feedback mechanism links UBC gene expression to ubiquitin levels by affecting RNA splicing rather than transcription

“…Furthermore, Ub overexpression led to a significant decrease in the Ub expression from the two polyubiquitin genes UBB and UBC . To the best of our knowledge, a similar evidence has only been described by the S. M. Wilson team in transgenic mice that expressed a HA-poly-Ub, under the control of a neuronal promoter 25,27 . The authors highlighted the selective sensitivity of neurons towards minimal changes in the Ub pool, which hence requires a strict control of Ub homeostasis in the neuronal system, but did not investigate the molecular mechanisms underlining this behavior.…”

“…Ubiquitin overexpression has been proved to be protective in the rescue from toxicity provoked by inhibitors of translation, which deplete free Ub by reducing its de novo synthesis 20 . On the other side, alteration of Ub homeostasis in mice, by overexpression of Ub in the neuronal compartment, impaired the synaptic function 27 . Moreover, when the authors investigated the potential effects of the higher Ub levels on the main components of the ubiquitin-proteasome system, they found a significant decrease in the expression of the endogenous polyubiquitin genes UBC and UBB , arguing that this is consistent with the need for a tightly regulated Ub homeostasis in neurons 25,27 .…”

“…On the other side, alteration of Ub homeostasis in mice, by overexpression of Ub in the neuronal compartment, impaired the synaptic function 27 . Moreover, when the authors investigated the potential effects of the higher Ub levels on the main components of the ubiquitin-proteasome system, they found a significant decrease in the expression of the endogenous polyubiquitin genes UBC and UBB , arguing that this is consistent with the need for a tightly regulated Ub homeostasis in neurons 25,27 . However, they did not further investigate the molecular mechanisms for this transcriptional downregulation.…”

Transcriptional expression changes during compensatory plasticity in the central nervous system of the adult cricket

“…Proteosomes can be recruited and sequestered at local synaptic sites in an activity-dependent manner (23), and the local function of the UPS system impacts synaptic strength and plasticity. For example, altering the level of ubiquitination of proteins at the synapse can alter baseline excitability and synaptic plasticity (24). These ubiquitin-related changes in synaptic strength can be pre-synaptic or postsynaptic (21).…”

Protein Homeostasis Networks and the Use of Yeast to Guide Interventions in Alzheimer’s Disease

“…The presence of the UPS in both the cytosol and nucleus indicates its significance during transcriptional and post-translational regulation of genes. The UPS plays a significant role in neuronal synapsis by regulating the DNA damage repair, neurotransmitter release, and membrane receptor turnover [62][63][64]. The degradation of protein due to UPS is dependent on the cellular processes and energy status.…”