The ubiquitin–proteasome cascade is required for mammalian long‐term memory formation

Lopez-Salon, Mariella; Alonso, Mariana; Vianna, Mônica Ryff Moreira Roca; Viola, Haydeé; Souza, Tadéu Mello e; Izquierdo, Iván; Pasquini, Juana M.; Medina, Jorge H.

doi:10.1046/j.0953-816x.2001.01806.x

Cited by 205 publications

(198 citation statements)

References 43 publications

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“…Remarkably, proteasomal impairment in individual neurons is sufficient to block activity-induced spine outgrowth (20). Moreover, the UPS is required for mammalian long-term memory formation (21). Furthermore, activity-dependent protein degradation is critical for the formation and stability of fear memory (22).…”

Section: Discussionmentioning

confidence: 99%

Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2

Gorrie¹,

Fecto²,

Radzicki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the gene encoding ubiquilin2 (UBQLN2) cause amyotrophic lateral sclerosis (ALS), frontotemporal type of dementia, or both. However, the molecular mechanisms are unknown. Here, we show that ALS/dementia-linked UBQLN2 P497H transgenic mice develop neuronal pathology with ubiquilin2/ubiquitin/p62-positive inclusions in the brain, especially in the hippocampus, recapitulating several key pathological features of dementia observed in human patients with UBQLN2 mutations. A major feature of the ubiquilin2-related pathology in these mice, and reminiscent of human disease, is a dendritic spinopathy with protein aggregation in the dendritic spines and an associated decrease in dendritic spine density and synaptic dysfunction. Finally, we show that the protein inclusions in the dendritic spines are composed of several components of the proteasome machinery, including Ub G76V -GFP, a representative ubiquitinated protein substrate that is accumulated in the transgenic mice. Our data, therefore, directly link impaired protein degradation to inclusion formation that is associated with synaptic dysfunction and cognitive deficits. These data imply a convergent molecular pathway involving synaptic protein recycling that may also be involved in other neurodegenerative disorders, with implications for development of widely applicable rational therapeutics.P rotein aggregates or inclusions with immunoreactivity to ubiquitin represent a common pathological hallmark in a broad range of late-onset neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) (1). However, the molecular mechanisms underlying the formation of these inclusions and their relationship to neuronal dysfunction and degeneration are poorly understood. Mutations in UBQLN2, which encodes the ubiquitin-like protein ubiquilin2 (UBQLN2), have been recently shown to cause a subset of ALS, FTD-type of dementia, or both (2, 3). Notably, mutations within and in close proximity to the PXX domain of ubiquilin2 appear to have high penetrance as shown in familial cases (2). The distribution of ubiquilin2-positive inclusions in the brain and spinal cord is well correlated with cognitive and motor symptoms of patients with diverse etiology, including chromosome 9 open reading frame 72 (C9ORF72)-linked cases (2, 4). The ubiquilin2-positive inclusions appear to cover a wide range of protein inclusions, including those without TAR DNA binding protein (TDP43) immunoreactivity (2, 4), suggesting a primary role for ubiquilin2 in inclusion formation and neurodegeneration. Therefore, understanding the pathophysiological basis of UBQLN2-linked dementia may provide mechanistic insight into the pathogenesis of neurodegenerative disorders and allow for the design of rational therapies. To this end, we developed and characterized mutant UBQLN2 transgenic mice. ResultsDevelopment of UBQLN2 P497H Transgenic Mice. Human UBQLN2 is an intronless gene. We analyzed the UBQLN2 promoter ...

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Section: Discussionmentioning

confidence: 99%

Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2

Gorrie¹,

Fecto²,

Radzicki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…When degradation of an inhibitory protein is necessary for memory consolidation, proteasome inhibitors blocked the formation of longterm memory (Chain et al, 1999;Lopez-Salon et al, 2001;Upadhya et al, 2004). Conversely, when UPS functioned as an inhibitory constraint, removal of constraint by proteasome inhibitor enhanced synaptic transmission and facilitated memory formation (Zhao et al, 2003;Yeh et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Augmentation of Fear Extinction by D-Cycloserine is Blocked by Proteasome Inhibitors

Mao

Lin

Gean

2008

Neuropsychopharmacol

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D-Cycloserine (DCS) has been shown to facilitate extinction of conditioned fear in rats and to improve fear reduction of social phobia and fear of heights in human studies. Here, we investigate the mechanism of DCS effect by measuring internalized GluR1 and GluR2 using cell-surface biotinylation techniques. DCS selectively increased NMDA receptor-mediated synaptic response without affecting AMPA receptor-mediated synaptic response. Low-frequency stimulation (LFS) when applied in the presence of DCS induced GluR1 and GluR2 internalization in the amygdala slices. Proteasome inhibitors block DCS facilitation of LFS-induced depotentiation and a reduction in surface levels of GluR1 and GluR2. Furthermore, DCS in combination with LFS reduced cellular levels of PSD-95 and synapse-associated protein 97 (SAP97), which were also blocked by proteasome inhibitors. In the in vivo experiments, DCS-induced reduction of fearpotentiated startle and reversal of conditioning-induced increase in surface expression of GluR1 were blocked by proteasome inhibitors. DCS-treated rats fail to exhibit reinstatement after US-alone presentations. These results suggest that DCS facilitates receptor internalization in the presence of extinction training, resulting in augmented reduction of startle potentiation.

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“…It was recently shown that inhibition of the proteasome system may enhance LTP induction (39) because of prevention of translation activator targeting (40). Multiple behavioral studies have also confirmed the crucial role of the ubiquitin-proteasome system in memory consolidation in the amygdala (23,41), hippocampus (24,42), and prefrontal cortex (32).…”

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confidence: 94%

Dynamics of Hippocampal Protein Expression During Long-term Spatial Memory Formation

Borovok

Nesher

Levin

et al. 2016

Molecular & Cellular Proteomics

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Spatial memory depends on the hippocampus, which is particularly vulnerable to aging. This vulnerability has implications for the impairment of navigation capacities in older people, who may show a marked drop in performance of spatial tasks with advancing age. Contemporary understanding of long-term memory formation relies on molecular mechanisms underlying long-term synaptic plasticity. With memory acquisition, activity-dependent changes occurring in synapses initiate multiple signal transduction pathways enhancing protein turnover. This enhancement facilitates de novo synthesis of plasticity related proteins, crucial factors for establishing persistent long-term synaptic plasticity and forming memory engrams. Extensive studies have been performed to elucidate molecular mechanisms of memory traces formation; however, the identity of plasticity related proteins is still evasive. In this study, we investigated protein turnover in mouse hippocampus during long-term spatial memory formation using the reference memory version of radial arm maze (RAM) paradigm. We identified 1592 proteins, which exhibited a complex picture of expression changes during spatial memory formation. Variable linear decomposition reduced significantly data dimensionality and enriched three principal factors responsible for variance of memory-related protein levels at (1) the initial phase of memory acquisition (165 proteins), (2) during the steep learning improvement (148 proteins), and (3) the final phase of the learning curve (123 proteins). Gene ontology and signaling pathways analysis revealed a clear correlation between memory improvement and learning phasecurbed expression profiles of proteins belonging to specific functional categories. We found differential enrichment of (1) Long-term synaptic plasticity is considered a cellular correlate of long-term memory (LTM) 1 . Contemporary understanding of memory formation is based on the initiation and maintenance of long-term synaptic plasticity (1-4), for which de novo protein synthesis is a vital requirement. De novo protein synthesis itself is secondary to activity-dependent changes in synapses that occur during learning processes. These activity changes trigger post-translational modifications of proteins initiating and sustaining multiple signal transduction pathways. In turn, these signaling pathways regulate changes in synaptic strength and connectivity by governing gene expression and protein translation (5-13). Depending on time elapsed since triggering of long-term synaptic plasticity, protein synthesis may be limited to the dendrites directly involved in the plasticity processes (14 -18). Multiple synaptic From the ‡Department

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The ubiquitin–proteasome cascade is required for mammalian long‐term memory formation

Cited by 205 publications

References 43 publications

Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2

Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2

Augmentation of Fear Extinction by D-Cycloserine is Blocked by Proteasome Inhibitors

Dynamics of Hippocampal Protein Expression During Long-term Spatial Memory Formation

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