Evidence for p62 aggregate formation: Role in cell survival

Paine, Michael G.; Babu, Jeganathan Ramesh; Seibenhener, M. Lamar; Wooten, Marie W.

doi:10.1016/j.febslet.2005.08.010

Cited by 51 publications

(53 citation statements)

References 24 publications

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“…5). The results are in line with previous reports that p62 can form fibrillar aggregates itself (39), and that p62 can oligomerize via its PB1 domain (40,41). The results from this study also show that p62 selectively interacted with the fALS-linked SOD1 mutants.…”

Section: Discussionsupporting

confidence: 82%

p62 Accumulates and Enhances Aggregate Formation in Model Systems of Familial Amyotrophic Lateral Sclerosis

Gál

Ström

Kilty

et al. 2007

Journal of Biological Chemistry

161

123

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron death. A hallmark of the disease is the appearance of protein aggregates in the affected motor neurons. We have found that p62, a protein implicated in protein aggregate formation, accumulated progressively in the G93A mouse spinal cord. The accumulation of p62 was in parallel to the increase of polyubiquitinated proteins and mutant SOD1 aggregates. Immunostaining studies showed that p62, ubiquitin, and mutant SOD1 co-localized in the protein aggregates in affected cells in G93A mouse spinal cord. The p62 protein selectively interacted with familial ALS mutants, but not WT SOD1. When p62 was co-expressed with SOD1 in NSC34 cells, it greatly enhanced the formation of aggregates of the ALS-linked SOD1 mutants, but not wild-type SOD1. Cell viability was measured in the presence and absence of overexpressed p62, and the results suggest that the large aggregates facilitated by p62 were not directly toxic to cells under the conditions in this study. Deletion of the ubiquitin-association (UBA) domain of p62 significantly decreased the p62-facilitated aggregate formation, but did not completely inhibit it. Further protein interaction experiments also showed that the truncated p62 with the UBA domain deletion remained capable of interacting with mutant SOD1. The findings of this study show that p62 plays a critical role in forming protein aggregates in familial ALS, likely by linking misfolded mutant SOD1 molecules and other cellular proteins together. Amyotrophic lateral sclerosis (ALS)3 is a progressive neurodegenerative disorder leading to the selective death of motor neurons (1, 2). The majority of cases are sporadic, but about 10% of all cases are familial (fALS). In ϳ20% of familial cases, a mutant allele of the copper-zinc superoxide dismutase (SOD1) enzyme has been identified (3-5). As of today, over 100 different mutations of SOD1 causing ALS have been reported, the majority of which are point mutations and act in a dominant fashion. Several ALS risk factors have been identified, but the etiology of the disease is largely unclear. A hallmark of the disease is the appearance of intracellular inclusions in degenerating motor neurons (6), both in the familial cases caused by mutations in SOD1 and in the more obscure sporadic cases (6 -11). The formation of such protein aggregates precedes neuronal death (12). The inclusions are typically SOD1 and ubiquitin immunoreactive in the mutant SOD1-mediated fALS cases (2, 7-9, 11-13). However, it is unclear how the SOD1 mutants form aggregates and whether other proteins play any role in the aggregation process or the aggregate-induced toxicity.p62 (also called sequestosome 1) was first identified as a phosphotyrosine-independent ligand for the Lck SH2 domain (14). It was later found to be a polyubiquitin-binding protein (15)(16)(17). The expression of p62 is up-regulated by several stress conditions, e.g. oxidative stress (18,19), proteasome inhibition (19 -21), or p...

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Section: Discussionsupporting

confidence: 82%

p62 Accumulates and Enhances Aggregate Formation in Model Systems of Familial Amyotrophic Lateral Sclerosis

Gál

Ström

Kilty

et al. 2007

Journal of Biological Chemistry

161

123

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“…WT +Cu 2+ and H50Q +Cu 2+ are the less-damaging aggregates and the ones that promote to a larger extent inclusion formation. Although so far we cannot identify the causes of this fact, similar observations were previously reported (62)(63)(64)(65)(66). Inclusion bodies were demonstrated to be protective in the case of the Huntington's disease-related protein huntingtin (67).…”

Section: Discussionsupporting

confidence: 49%

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Villar‐Piqué

Fonseca

Sant’Anna

et al. 2016

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

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Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors. Here, we analyzed these factors and found that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q aSyn mutation induces a significant alteration in the aggregation properties of aSyn. We compared the aggregation of WT and H50Q aSyn with and without copper, and assessed the effects of the resultant protein species when applied to primary neuronal cultures. The presence of copper induces the formation of structurally different and less-damaging aSyn aggregates. Interestingly, these aggregates exhibit a stronger capacity to induce aSyn inclusion formation in recipient cells, which demonstrates that the structural features of aSyn species determine their effect in neuronal cells and supports a lack of correlation between toxicity and inclusion formation. In total, our study provides strong support in favor of the hypothesis that protein aggregation is not a primary cause of cytotoxicity.α-synuclein | copper | H50Q mutation | inclusions | protein aggregation

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“…Aggregates analyzed in plaques from brains of Alzheimer's disease patients or in Lewy bodies from Parkinson's disease samples contain SQSTM1 as a major constituent (Kuusisto et al, 2001;Nakaso et al, 2004). Removal of SQSTM1 results in increased aggregate formation in the cell, whereas overexpression of SQSTM1 results in increased aggregate clearance (Paine et al, 2005) leading to the proposal that SQSTM1 can function in garbage packing for the eventual disposal of toxic proteins (Moscat and Diaz-Meco, 2009). SQSTM1 is also involved in the elimination of defective mitochondria through modulation of Parkin-and PINK1-mediated mitochondrial clearance (Geisler et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Interaction of SQSTM1 with the motor protein dynein: SQSTM1 is required for normal dynein function and trafficking

Calderilla-Barbosa

Seibenhener

et al. 2014

Journal of Cell Science

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BSTRACTThe dynein motor protein complex is required for retrograde transport of vesicular cargo and for transport of aggregated proteins along microtubules for processing and degradation at perinuclear aggresomes. Disruption of this process leads to dysfunctional endosome accumulation and increased protein aggregation in the cell cytoplasm, both pathological features of neurodegenerative diseases. However, the exact mechanism of dynein functionality in these pathways is still being elucidated. Here, we show that the scaffolding protein SQSTM1 directly interacts with dynein through a previously unidentified dynein-binding site. This interaction is independent of HDAC6, a known interacting protein of both SQSTM1 and dynein. However, knockdown of HDAC6 increases the interaction of SQSTM1 with dynein, indicating a possible competitive interaction. Using different dynein cargoes, we show that SQSTM1 is required for proper dynein motility and trafficking along microtubules. Based on our results, we propose a new model of competitive interaction between SQSTM1 and HDAC6 with dynein. In this model, SQSTM1 would not only affect the association of polyubiquitylated protein aggregates and endosomes with dynein, but would also be required for normal dynein function.

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Evidence for p62 aggregate formation: Role in cell survival

Cited by 51 publications

References 24 publications

p62 Accumulates and Enhances Aggregate Formation in Model Systems of Familial Amyotrophic Lateral Sclerosis

p62 Accumulates and Enhances Aggregate Formation in Model Systems of Familial Amyotrophic Lateral Sclerosis

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Interaction of SQSTM1 with the motor protein dynein: SQSTM1 is required for normal dynein function and trafficking

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