Polyglutamine Expansion, Protein Aggregation, Proteasome Activity, and Neural Survival

Qian, Dali; Lewis, Jennifer; Strum, Kenneth M.; Dimayuga, Edgardo; Bruce‐Keller, Annadora J.; Dunn, Jay C.; Keller, Jeffrey N.

doi:10.1074/jbc.m107706200

Cited by 103 publications

(72 citation statements)

References 46 publications

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“…3). These observations are also consistent with the aggregation and toxicity of expanded polyglutamine proteins in cell and animal models (16,17,37,38), as well as disease tissue (8 -10, 36). In previous work, it has been suggested by ourselves and others that expansion of the polyglutamine tract may destabilize the native protein, leading to aggregation and fibrillization (19,22,24).…”

Section: Kinetic Analysis Of Acid-induced Denaturation Of Ataxin-3-supporting

confidence: 76%

Polyglutamine Expansion in Ataxin-3 Does Not Affect Protein Stability

Chow

Ellisdon

Cabrita

et al. 2004

Journal of Biological Chemistry

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Polyglutamine proteins that cause neurodegenerative disease are known to form proteinaceous aggregates, such as nuclear inclusions, in the neurons of affected patients. Although polyglutamine proteins have been shown to form fibrillar aggregates in a variety of contexts, the mechanisms underlying the aberrant conformational changes and aggregation are still not well understood. In this study, we have investigated the hypothesis that polyglutamine expansion in the protein ataxin-3 destabilizes the native protein, leading to the accumulation of a partially unfolded, aggregation-prone intermediate. To examine the relationship between polyglutamine length and native state stability, we produced and analyzed three ataxin-3 variants containing 15, 28, and 50 residues in their respective glutamine tracts. At pH 7.4 and 37°C, Atax3(Q50), which lies within the pathological range, formed fibrils significantly faster than the other proteins. Somewhat surprisingly, we observed no difference in the acid-induced equilibrium and kinetic un/folding transitions of all three proteins, which indicates that the stability of the native conformation was not affected by polyglutamine tract extension. This has led us to reconsider the mechanisms and factors involved in ataxin-3 misfolding, and we have developed a new model for the aggregation process in which the pathways of un/folding and misfolding are distinct and separate. Furthermore, given that native state stability is unaffected by polyglutamine length, we consider the possible role and influence of other factors in the fibrillization of ataxin-3.

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Section: Kinetic Analysis Of Acid-induced Denaturation Of Ataxin-3-supporting

confidence: 76%

Polyglutamine Expansion in Ataxin-3 Does Not Affect Protein Stability

Chow

Ellisdon

Cabrita

et al. 2004

Journal of Biological Chemistry

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“…Although prolonged exposure to H 2 O 2 and other ROS, with associated inhibition of proteasomal activity, is thought to contribute to accelerating aging, DNA damage, and neurodegen- erative disorders (36,65), transient reduction of 26 S proteasomal activity may be beneficial in treating malignancies and acute life-threatening inflammatory conditions. For example, because the ubiquitin/proteasome pathway participates in cell cycle progression, inhibition of proteasomal function, such as that produced by the pharmacologic agent Bortezomib, has been shown to be useful as a chemotherapeutic approach for multiple myeloma (21,22).…”

Section: Discussionmentioning

confidence: 99%

S-Glutathionylation of the Rpn2 Regulatory Subunit Inhibits 26 S Proteasomal Function

Żmijewski

Banerjee²,

Abraham

2009

Journal of Biological Chemistry

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Although increased intracellular concentrations of hydrogen peroxide (H 2 O 2 ) are associated with inhibition of 26 S proteasomal activity, the mechanisms responsible for such effects have not been well delineated. In the present studies, we found that direct exposure of purified 26 S proteasomes to H 2 O 2 had negligible effects on their activity, whereas incubation with glutathione and H 2 O 2 produced >80% decrease in chymotrypsin-like and trypsin-like activities. Rpn1 and Rpn2, which are subunits of the 19 S regulatory particle, undergo S-glutathionylation after exposure of purified 26 S proteasomes to glutathione and H 2 O 2 , as well as in HEK 293 cells and neutrophils incubated with H 2 O 2 . Increased oxidation of Rpn1 and Rpn2 cysteine thiols was also found in lung extracts from mice in which catalase was inactivated, a condition associated with augmented intracellular concentrations of H 2 O 2 and diminished 26 S proteasomal activity. Although unoxidized Rpn2 enhanced 20 S proteolytic function in vitro, such potentiation was not found when the 20 S core particle was incubated with oxidized Rpn2. The composition of 26 S proteasomes was not altered after exposure to glutathione and H 2 O 2 , with similar amounts of Rpn1 and Rpn2 in control or oxidized 26 S proteasomal complexes. These findings identify S-glutathionylation of Rpn2 as a contributory mechanism for H 2 O 2 -induced inhibition of 26 S proteasomal function.The ubiquitin-proteasomal system is a major pathway for protein degradation and is involved in multiple cellular processes, including cell cycle control, expression of cell surface receptors, and regulation of intracellular levels of structural and regulatory proteins and transcription factors (1-6). The 26 S proteasome is composed of two main components, a proteolytic 20 S core particle (CP) 2 and an ATPase containing 19 S regulatory particle (RP) (7-10). Ubiquitinated proteins are unfolded in the 19 S RP and then translocated into the 20 S CP where they are degraded. The 20 S CP is composed of four heptameric rings of ␣ and ␤ subunits, with the two inner ␤ rings having proteolytic activity. The 19 S RP consists of a lid and base subcomplex, with the base subcomplex, including the nonenzymatic Rpn1 and Rpn2 toroids, surrounded by six AAA-type ATPases. Rpn1 and Rpn2 appear to play a major regulatory role by modulating the translocation and subsequent degradation of ubiquitinated substrates in the proteolytic core of the 20 S CP (7,(11)(12)(13)(14)(15).Decreased 26 S proteasomal activity, resulting in the accumulation of intracellular proteins, has been associated with aging (16, 17) and with pathophysiologic processes, including heart failure, neurodegenerative diseases, and alcohol induced liver injury (18 -20). A number of recent studies have shown that time-limited inhibition of the 26 S proteasome is beneficial as a therapeutic intervention for malignancies, such as multiple myeloma, and in reducing inflammation and cell injury associated with ischemia-reperfusion injury and transplanta...

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“…Total RNA was isolated from the inferior parietal lobule as described previously by our laboratory (Ding et al, 2002). The primers for individual rRNA or tRNA species are provided below.…”

Section: Methodsmentioning

confidence: 99%

“…Whole-tissue lysates were generated from the inferior parietal lobule of each patient, with 50 g of total proteins loaded for Western blot analysis as described previously by our laboratory (Ding et al, 2002). Antibodies against FK506-binding protein-rapamycin-associated protein (FRAP), phosphorylated p70 S6 kinase, phosphorylated eukaryotic initiation factor 2 (eIF2␣), and phosphorylated double-stranded RNA-activated protein kinase (PKR) were purchased from Santa Cruz Biotechnology(Santa Cruz, CA) and Cell Signaling Technology (Beverly, MA).…”

Section: Methodsmentioning

confidence: 99%

Ribosome Dysfunction Is an Early Event in Alzheimer's Disease

Qian¹,

Markesbery²,

Chen³

et al. 2005

J. Neurosci.

388

333

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Alzheimer's disease (AD) is a progressive and devastating disorder that is often preceded by mild cognitive impairment (MCI). In the present study, we report that in multiple cortical areas of MCI and AD subjects, there is a significant impairment in ribosome function that is not observed in the cerebellum of the same subjects. The impairment in ribosome function is associated with a decreased rate and capacity for protein synthesis, decreased ribosomal RNA and tRNA levels, and increased RNA oxidation. No alteration in the level of initiation factors was observed in the brain regions exhibiting impairments in protein synthesis. Together, these data indicate for the first time that impairments in protein synthesis may be one of the earliest neurochemical alterations in AD and directly demonstrate that the polyribosome complex is adversely affected early in the development of AD. These data have important implications for AD studies involving proteomics and studies analyzing proteolysis in AD, indicate that oxidative damage may contribute to decreased protein synthesis, and suggest a role for alterations in protein synthesis as a novel contributor to the onset and development of AD.

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Polyglutamine Expansion, Protein Aggregation, Proteasome Activity, and Neural Survival

Cited by 103 publications

References 46 publications

Polyglutamine Expansion in Ataxin-3 Does Not Affect Protein Stability

Polyglutamine Expansion in Ataxin-3 Does Not Affect Protein Stability

S-Glutathionylation of the Rpn2 Regulatory Subunit Inhibits 26 S Proteasomal Function

Ribosome Dysfunction Is an Early Event in Alzheimer's Disease

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