Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation

Babu, Jeganathan Ramesh; Geetha, Thangiah; Wooten, Marie W.

doi:10.1111/j.1471-4159.2005.03181.x

Cited by 282 publications

(261 citation statements)

References 41 publications

(106 reference statements)

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“…Utilizing a ubiquitin-binding pull-down assay (Meller et al, 2006), we determined changes in protein ubiquitination after preconditioning ischemia. P62 (sequestome-1) shuttles ubiquitinated proteins to the proteasome (Babu et al, 2005). The pull-down of ubiquitinated proteins by P62 ubiquitin binding domain-conjugated agarose beads was confirmed in an ex vivo assay (supplemental Fig.…”

Section: Proteomic Analysis Of Ubiquitinated Proteins After Preconditmentioning

confidence: 91%

Ubiquitin–Proteasome-Mediated Synaptic Reorganization: A Novel Mechanism Underlying Rapid Ischemic Tolerance

Meller¹,

Thompson²,

Lusardi³

et al. 2008

J. Neurosci.

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Ischemic tolerance is an endogenous neuroprotective mechanism in brain and other organs, whereby prior exposure to brief ischemia produces resilience to subsequent normally injurious ischemia. Although many molecular mechanisms mediate delayed (genemediated) ischemic tolerance, the mechanisms underlying rapid (protein synthesis-independent) ischemic tolerance are relatively unknown. Here we describe a novel mechanism for the induction of rapid ischemic tolerance mediated by the ubiquitin-proteasome system. Rapid ischemic tolerance is blocked by multiple proteasome inhibitors [carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG132), MG115 (carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal), and clasto-lactacystin-␤-lactone].A proteomics strategy was used to identify ubiquitinated proteins after preconditioning ischemia. We focused our studies on two actin-binding proteins of the postsynaptic density that were ubiquitinated after rapid preconditioning: myristoylated, alanine-rich C-kinase substrate (MARCKS) and fascin. Immunoblots confirm the degradation of MARCKS and fascin after preconditioning ischemia. The loss of actin-binding proteins promoted actin reorganization in the postsynaptic density and transient retraction of dendritic spines. This rapid and reversible synaptic remodeling reduced NMDA-mediated electrophysiological responses and renders the cells refractory to NMDA receptor-mediated toxicity. The dendritic spine retraction and NMDA neuroprotection after preconditioning ischemia are blocked by actin stabilization with jasplakinolide, as well as proteasome inhibition with MG132. Together these data suggest that rapid tolerance results from changes to the postsynaptic density mediated by the ubiquitin-proteasome system, rendering neurons resistant to excitotoxicity.

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Section: Proteomic Analysis Of Ubiquitinated Proteins After Preconditmentioning

confidence: 91%

Ubiquitin–Proteasome-Mediated Synaptic Reorganization: A Novel Mechanism Underlying Rapid Ischemic Tolerance

Meller¹,

Thompson²,

Lusardi³

et al. 2008

J. Neurosci.

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“…A different aggregation-prone protein characterizes the pathology of each of these diseases, but virtually all these protein aggregates associate with p62/ SQSTM1 (Kuusisto et al 2001;Mizuno et al 2006). The presence of p62/SQSTM1 in pathological protein inclusions initially suggested a causal role in their formation (Kuusisto et al 2002), but recent evidence shows that p62/SQSTM1 actually mediates the degradation of at least some of these aggregate-prone proteins (Bjorkoy et al 2005;Babu et al 2005): in fact, p62/SQSTM1 shuttles the AD-associated protein tau to the proteasome for degradation (Babu et al 2005). This suggests that p62/SQSTM1 has a protective role in AD.…”

Section: Neurodegenerative Diseasesmentioning

confidence: 99%

p62/SQSTM1 at the interface of aging, autophagy, and disease

Bitto

Lerner

Nacarelli

et al. 2014

AGE

124

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Advanced age is characterized by increased incidence of many chronic, noninfectious diseases that impair the quality of living of the elderly and pose a major burden on the healthcare systems of developed countries. These diseases are characterized by impaired or altered function at the tissue and cellular level, which is a hallmark of the aging process. Age-related impairments are likely due to loss of homeostasis at the cellular level, which leads to the accumulation of dysfunctional organelles and damaged macromolecules, such as proteins, lipids, and nucleic acids. Intriguingly, aging and age-related diseases can be delayed by modulating nutrient signaling pathways converging on the target of rapamycin (TOR) kinase, either by genetic or dietary intervention. TOR signaling influences aging through several potential mechanisms, such as autophagy, a degradation pathway that clears the dysfunctional organelles and damaged macromolecules that accumulate with aging. Autophagy substrates are targeted for degradation by associating with p62/SQSTM1, a multidomain protein that interacts with the autophagy machinery. p62/SQSTM1 is involved in several cellular processes, and its loss has been linked to accelerated aging and to age-related pathologies. In this review, we describe p62/SQSTM1, its role in autophagy and in signaling pathways, and its emerging role in aging and age-associated pathologies. Finally, we propose p62/ SQSTM1 as a novel target for aging studies and ageextending interventions.

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“…This NT controls the endogenous tau synthesis either directly, by up-regulation of gene transcription (Drubin et al, 1985;Sadot et al, 1996), or indirectly, by its ubiquitination and proteosomal degradation (Babu et al, 2005). The phosphorylation state of tau-which critically controls its physiopathology leading to selfaggregation and/or reduced assembly and stability of microtubules used as tracks for axonal trafficking (Stoothoff et al, 2005)-is also regulated by NGF deprivation in vitro (Nuydens et al, 1997;Shelton and Johnson, 2001) as well as in vivo Capsoni et al, 2002a,b).…”

Section: Ngf and Tau Protein Metabolismmentioning

confidence: 99%

Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease

Calissano

Matrone

Amadoro

2010

Developmental Neurobiology

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Converging lines of evidence on the possible connection between NGF signaling and Alzheimer's diseases (AD) are unraveling new facets which could depict this neurotrophin (NTF) in a more central role. AD animal models have provided evidence that a shortage of NGF supply may induce an AD-like syndrome. In vitro experiments, moreover, are delineating a possible temporal and causal link between APP amiloydogenic processing and altered post-translational tau modifications. After NGF signaling interruption, the pivotal upstream players of the amyloid cascade (APP, b-secretase, and active form of c-secretase) are up-regulated, leading to an increased production of amyloid b peptide (Ab) and to its intracellular aggregation in molecular species of different sizes. Contextually, the Ab released pool generates an autocrine toxic loop in the same healthy neurons. At the same time tau protein undergoes anomalous, GSKb-mediated, phosphorylation at specific pathogenetic sites (Ser262 and Thr 231), caspase(s) and calpain-I-mediated truncation, detachment from microtubules with consequent cytoskeleton collapse and axonal transport impairment. All these events are inhibited when the amyloidogenic processing is reduced by b and c secretase inhibitors or anti-Ab antibodies and appear to be causally correlated to TrkA, p75CTF, Ab, and PS1 molecular association in an Ab-mediated fashion. In this scenario, the so-called trophic action exerted by NGF (and possibly also by other neurotrophins) in these targets neurons is actually the result of an anti-amyloidogenic activity. '

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Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation

Cited by 282 publications

References 41 publications

Ubiquitin–Proteasome-Mediated Synaptic Reorganization: A Novel Mechanism Underlying Rapid Ischemic Tolerance

Ubiquitin–Proteasome-Mediated Synaptic Reorganization: A Novel Mechanism Underlying Rapid Ischemic Tolerance

p62/SQSTM1 at the interface of aging, autophagy, and disease

Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease

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