The Proteasome and Ageing.

The proteasome is a multi-subunit proteolytic complex that functions to degrade normal proteins for physiological regulation and to eliminate abnormal proteins for cellular protection. Generally, the proteasome targets substrate proteins that are marked by attachment of multiple ubiquitin molecules. In various types of cells in an organism, damage to proteins occurs both from internal sources such as reactive oxygen species and from external ones such as UV radiation from the sun.

Degradation of Transcriptional Repressor ATF4 during Long-Term Synaptic Plasticity.

Maintenance of long-term synaptic plasticity requires gene expression mediated by cAMP-responsive element binding protein (CREB). Gene expression driven by CREB can commence only if the inhibition by a transcriptional repressor activating transcription factor 4 (ATF4; also known as CREB2) is relieved. Previous research showed that the removal of ATF4 occurs through ubiquitin-proteasome-mediated proteolysis.

Perturbations of Ubiquitin-Proteasome-Mediated Proteolysis in Aging and Alzheimer's Disease.

The ubiquitin-proteasome pathway (UPP) has multiple roles in the normal nervous system, including the development of synaptic connections and synaptic plasticity. Research over the past several years has indicated a role for the UPP in aging without any overt pathology in the brain. In addition, malfunction of the UPP is implicated in Alzheimer's disease (AD) and dementia associated with it.

Recent developments in transcriptional and translational regulation underlying long-term synaptic plasticity and memory.

Formation of long-term synaptic plasticity that underlies long-term memory requires new protein synthesis. Years of research has elucidated some of the transcriptional and translational mechanisms that contribute to the production of new proteins. Early research on transcription focused on the transcription factor cAMP-responsive element binding protein.

Proteasome limits plasticity-related signaling to the nucleus in the hippocampus.

Proteolysis by the ubiquitin-proteasome pathway has pleiotropic effects on both induction and maintenance of long-term synaptic plasticity. In this study, we examined the effect of proteasome inhibition on signaling to the nucleus during late-phase long-term potentiation. When a subthreshold L-LTP induction protocol was used, proteasome inhibition led to a significant increase in phosphorylated CREB (pCREB) in the nucleus.

Age-dependent changes in brain hydration and synaptic plasticity.

Aging in humans and animals is associated with gradual and variable changes in some cognitive functions, but what causes them and explains individual variations remains unclear. Hydration decreases with aging but whether dehydration contributes to cognitive dysfunction is not known. The brain hydration of aging mice was determined by colloidosmotic-pressure titration.

Proteolysis, synaptic plasticity and memory.

Protein degradation has many critical functions in the nervous system such as refinement of synaptic connections during development and synaptic plasticity and memory in the adult organisms. A major cellular machinery of proteolysis is the ubiquitin-proteasome pathway (UPP). The UPP precisely regulates proteolysis by covalently attaching ubiquitin, a small protein, to substrates through sequential enzymatic reactions and the proteins marked with the ubiquitin tag are degraded by complex containing many subunits called the proteasome.

The proteasome and epigenetics: zooming in on histone modifications.

The proteasome is a structural complex of many proteins that degrades substrates marked by covalent linkage to ubiquitin. Many years of research has shown a role for ubiquitin-proteasome-mediated proteolysis in synaptic plasticity and memory mainly in degrading synaptic, cytoplasmic and nuclear proteins. Recent work indicates that the proteasome has wider proteolytic and non-proteolytic roles in processes such as histone modifications that affect synaptic plasticity and memory.

Expression of the Longest RGS4 Splice Variant in the Prefrontal Cortex Is Associated with Single Nucleotide Polymorphisms in Schizophrenia Patients.

The Regulator of G protein signaling 4 (RGS4) gene is a candidate susceptibility gene for schizophrenia (SCZ). Previous studies showed that the mRNA level of the longest splice variant RGS4-1 was decreased in the dorsolateral prefrontal cortex (DLPFC) of SCZ patients compared with healthy controls. In this pilot study, we examined the possible mechanisms of RGS4-1 mRNA reduction in SCZ.

Proteasome inhibition augments new protein accumulation early in long-term synaptic plasticity and rescues adverse Aβ effects on protein synthesis.

Protein degradation plays a critical role in synaptic plasticity, but the molecular mechanisms are not well understood. Previously we showed that proteasome inhibition enhances the early induction part of long-term synaptic plasticity for which protein synthesis is essential. In this study, we tested the effect of proteasome inhibition on protein synthesis using a chemically induced long-lasting synaptic plasticity (cLTP) in the murine hippocampus as a model system.

Proteasome regulates transcription-favoring histone methylation, acetylation and ubiquitination in long-term synaptic plasticity.

Histone modifications, such as lysine methylation, acetylation and ubiquitination, are epigenetic tags that shape the chromatin landscape and regulate transcription required for synaptic plasticity and memory. Here, we show that transcription-promoting histone H3 trimethylated at lysine 4 (H3K4me3), histone H3 acetylated at lysine 9 and 14 (H3K9/14ac), and histone H2B monoubiquitinated at lysine 120 (H2BK120ub) are enhanced after the induction of long-lasting chemically-induced long-term potentiation (cLTP) in the murine hippocampus. While H3K4me3 and H3K9/14ac were transiently upregulated, H2BK120ub levels oscillated after cLTP induction.

Local ubiquitin-proteasome-mediated proteolysis and long-term synaptic plasticity.

The ubiquitin-proteasome pathway (UPP) of protein degradation has many roles in synaptic plasticity that underlies memory. Work on both invertebrate and vertebrate model systems has shown that the UPP regulates numerous substrates critical for synaptic plasticity. Initial research took a global view of ubiquitin-protein degradation in neurons.

Proteasome regulates the mediators of cytoplasmic polyadenylation signaling during late-phase long-term potentiation.

The ubiquitin-proteasome pathway is essential for long-term synaptic plasticity, but its exact roles remain unclear. Previously we established that proteasome inhibition increased the early, induction part of late-phase long-term potentiation (L-LTP) but blocks the late, maintenance part. Our prior work also showed that the proteasome modulates components of the mammalian target of rapamycin pathway for translation.

Proteasome modulates positive and negative translational regulators in long-term synaptic plasticity.

Proteolysis by the ubiquitin-proteasome pathway appears to have a complex role in synaptic plasticity, but its various functions remain to be elucidated. Using late phase long-term potentiation (L-LTP) in the hippocampus of the mouse as a model for long-term synaptic plasticity, we previously showed that inhibition of the proteasome enhances induction but blocks maintenance of L-LTP. In this study, we investigated the possible mechanisms by which proteasome inhibition has opposite effects on L-LTP induction and maintenance.

Expression profiling reveals differential gene induction underlying specific and non-specific memory for pheromones in mice.

Memory for the mating male's pheromones in female mice is thought to require synaptic changes in the accessory olfactory bulb (AOB). Induction of this memory depends on release of glutamate in response to pheromonal exposure coincident with release of norepinephrine (NE) in the AOB following mating. A similar memory for pheromones can also be induced artificially by local infusion of the GABA(A) receptor antagonist bicuculline into the AOB.

Role of ubiquitin-proteasome-mediated proteolysis in nervous system disease.

Proteolysis by the ubiquitin-proteasome pathway (UPP) is now widely recognized as a molecular mechanism controlling myriad normal functions in the nervous system. Also, this pathway is intimately linked to many diseases and disorders of the brain. Among the diseases connected to the UPP are neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases.

The ubiquitin-proteasome pathway and synaptic plasticity.

Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wide-ranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for degradation by a multisubunit complex called the proteasome. Linkage of ubiquitin to protein substrates is highly specific and occurs through a series of well-orchestrated enzymatic steps.

Expression of RGS4 splice variants in dorsolateral prefrontal cortex of schizophrenic and bipolar disorder patients.

Background: Previous molecular and genetic studies have implicated RGS4 (regulator of G protein signaling 4) in schizophrenia (SCZ) and bipolar disorder (BPD), but the role of RGS4 in the pathology of the two disorders remains controversial. Recently we identified five different RGS4 splice variants in the human brain. In this study we tested whether expression of specific RGS4 splice variants is altered in the prefrontal cortex of schizophrenic and BPD subjects.

Proteasome inhibition enhances the induction and impairs the maintenance of late-phase long-term potentiation.

Protein degradation by the ubiquitin-proteasome pathway plays important roles in synaptic plasticity, but the molecular mechanisms by which proteolysis regulates synaptic strength are not well understood. We investigated the role of the proteasome in hippocampal late-phase long-term potentiation (L-LTP), a model for enduring synaptic plasticity. We show here that inhibition of the proteasome enhances the induction of L-LTP, but inhibits its maintenance.

Role of the ubiquitin proteasome system in Alzheimer's disease.

Though Alzheimer's disease (AD) is a syndrome with well-defined clinical and neuropathological manifestations, an array of molecular defects underlies its pathology. A role for the ubiquitin proteasome system (UPS) was suspected in the pathogenesis of AD since the presence of ubiquitin immunoreactivity in AD-related neuronal inclusions, such as neurofibrillary tangles, is seen in all AD cases. Recent studies have indicated that components of the UPS could be linked to the early phase of AD, which is marked by synaptic dysfunction, as well as to the late stages of the disease, characterized by neurodegeneration.

The ubiquitin-proteasome pathway in health and disease of the nervous system.

In recent years, proteolysis by the ubiquitin-proteasome pathway has attained prominence as a new molecular mechanism that regulates many vital functions of the nervous system, including development of synaptic connections and synaptic plasticity. Here, we review the latest findings on the role of proteolysis in sculpting the nervous system through control of axonal growth, axonal and dendritic pruning, and regulation of synaptic size and number. We also discuss how protein degradation functions in synaptic plasticity and the roles of local proteolysis in neuronal compartments.

Full length cloning and expression analysis of splice variants of regulator of G-protein signaling RGS4 in human and murine brain.

RGS4 (regulator of G protein signaling 4) protein is a GTPase-activating protein specific for Gi/o and Gq alpha subunits. It is highly expressed in brain but the mechanisms by which RGS4 expression is regulated remain unknown. RGS4 is associated with schizophrenia either through heritable genetic polymorphisms or as a co-regulated mediator of the pathology, and may play a role in other brain diseases.

Proteasome and transcription: a destroyer goes into construction.

The proteasome is a proteolytic complex that is known to degrade proteins marked by the attachment of ubiquitin. Recently, it has become apparent that the proteasome has non-proteolytic roles. Several studies have implicated the proteasome in the regulation of transcription.

Differential regulation of proteasome activity in the nucleus and the synaptic terminals.

Proteasome is a multi-subunit proteolytic complex that degrades proteins covalently linked to multiple molecules of ubiquitin. Earlier studies showed a role for the ubiquitin-proteasome pathway in several models of long-term memory and other forms of synaptic plasticity. In Aplysia, the ubiquitin-proteasome pathway has been shown to contribute to the induction of long-term facilitation.