Expanded Polyglutamine-containing N-terminal Huntingtin Fragments Are Entirely Degraded by Mammalian Proteasomes

Juenemann, Katrin; Schipper-Krom, Sabine; Wiemhoefer, Anne; Kloß, Alexander; Sanz, Alicia Sanz; Reits, Eric

doi:10.1074/jbc.m113.486076

Cited by 67 publications

(63 citation statements)

References 82 publications

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“…Moreover, mutant huntingtin fragments have not been found to inhibit degradation of ubiquitylated substrates by the 26S proteasome in vitro (Hipp et al, 2012). Whether or not polyQ proteins can be degraded by the mammalian proteasome has been the subject of a considerable debate (Venkatraman et al, 2004; Pratt and Rechsteiner, 2008; Juenemann et al, 2013). Puromycin-sensitive aminopeptidase has been identified as the main cytosolic protease to efficiently clear expanded polyQ peptides generated by the proteasome in vitro (Bhutani et al, 2007).…”

Section: Proteasome Activity In Neurodegenerative Diseasesmentioning

confidence: 99%

“…However, the question remains whether or not the proteasome can efficiently degrade disease-linked proteins. Some studies have suggested that the proteasome cannot degrade the polyQ proteins (Dyer and McMurray, 2001; Jana et al, 2001; Holmberg et al, 2004; Venkatraman et al, 2004) whereas others other reports show that they can be efficiently degraded by the proteasome as long as they remain in a soluble state (Verhoef et al, 2002; Kaytor et al, 2004; Michalik and Van Broeckhoven, 2004; Juenemann et al, 2013; Tsvetkov et al, 2013). Also, α-synuclein, expression levels of which can predispose individuals to PD (Singleton et al, 2003), can be degraded by the proteasome (Bennett et al, 1999), suggesting that other aggregation-prone proteins can be targeted by the UPS.…”

Section: Reducing Levels Of Neurodegeneration-associated Proteinsmentioning

confidence: 99%

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The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution

Dantuma

Bott

2014

Front. Mol. Neurosci.

266

208

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The ubiquitin-proteasome system (UPS) has been implicated in neurodegenerative diseases based on the presence of deposits consisting of ubiquitylated proteins in affected neurons. It has been postulated that aggregation-prone proteins associated with these disorders, such as α-synuclein, β-amyloid peptide, and polyglutamine proteins, compromise UPS function, and delay the degradation of other proteasome substrates. Many of these substrates play important regulatory roles in signaling, cell cycle progression, or apoptosis, and their inadvertent stabilization due to an overloaded and improperly functioning UPS may thus be responsible for cellular demise in neurodegeneration. Over the past decade, numerous studies have addressed the UPS dysfunction hypothesis using various model systems and techniques that differ in their readout and sensitivity. While an inhibitory effect of some disease proteins on the UPS has been demonstrated, increasing evidence attests that the UPS remains operative in many disease models, which opens new possibilities for treatment. In this review, we will discuss the paradigm shift that repositioned the UPS from being a prime suspect in the pathophysiology of neurodegeneration to an attractive therapeutic target that can be harnessed to accelerate the clearance of disease-linked proteins.

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Section: Proteasome Activity In Neurodegenerative Diseasesmentioning

confidence: 99%

Section: Reducing Levels Of Neurodegeneration-associated Proteinsmentioning

confidence: 99%

The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution

Dantuma

Bott

2014

Front. Mol. Neurosci.

266

208

View full text Add to dashboard Cite

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“…Filter Trap Assay-The filter trap assay was carried out essentially as described by Juenemann et al (28). Briefly, the pellet fraction of the cell lysate was suspended in the benzonase buffer (1 mM MgCl 2 , 50 mM Tris/HCl, pH 8.0) and treated with an RNase/DNase mixture (50 units each; Fermentas) and incubated for 1 h at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Decreased O-Linked GlcNAcylation Protects from Cytotoxicity Mediated by Huntingtin Exon1 Protein Fragment

Kumar

Singh

Parihar

et al. 2014

Journal of Biological Chemistry

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Background:Earlier reports indicate that O-GlcNAcylation might be protective in neurodegenerative disorders. Results: Suppressing O-GlcNAcylation modulates autophagy to enhance the viability of neuronal cells expressing cytotoxic mutant huntingtin exon 1 protein (mHtt). Conclusion: O-GlcNAcylation regulates the clearance of mHtt by modulating the fusion of autophagosomes with lysosomes. Significance: This regulatory mechanism emerges as a novel therapeutic strategy for Huntington disease.

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“…Although it appears unlikely that a fully intact aggresome can be enveloped into a single autophagosome, smaller aggregated structures up to 1 μm in diameter have been found within these double-membraned structures (Filimonenko et al, 2010). Earlier structures that contribute to aggregate formation, such as misfolded monomeric or perhaps early oligomeric states of an aggregating proteins, might also depend on other degradative pathways, such as the proteasome or chaperone-mediated autophagy (Mak et al, 2010;Ortega and Lucas, 2014;Juenemann et al, 2013;Schipper-Krom et al, 2014;Thompson et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Distinguishing aggregate formation and aggregate clearance using cell-based assays

Eenjes

Dragich

Kampinga

et al. 2016

Journal of Cell Science

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The accumulation of ubiquitylated proteinaceous inclusions represents a complex process, reflecting the disequilibrium between aggregate formation and aggregate clearance. Although decreasing aggregate formation or augmenting aggregate clearance will ultimately lead to a diminished aggregate burden, in terms of disease pathogenesis, the different approaches can have distinct outcomes. Using a novel cellbased assay that can distinguish newly formed versus preformed inclusions, we demonstrate that two proteins previously implicated in the autophagic clearance of expanded polyglutamine inclusions, HspB7 and Alfy (also known as WDFY3), actually affect very distinct cellular processes to affect aggregate burden. Using this cell-based assay, we also establish that constitutive expression of the aggregation-prone protein can measurably slow the elimination of protein aggregates, given that not all aggregates appear to be available for degradation. This new assay can therefore not only determine at what step a modifier might influence aggregate burden, but also can be used to provide new insights into how protein aggregates are targeted for degradation.

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Expanded Polyglutamine-containing N-terminal Huntingtin Fragments Are Entirely Degraded by Mammalian Proteasomes

Cited by 67 publications

References 82 publications

The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution

The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution

Decreased O-Linked GlcNAcylation Protects from Cytotoxicity Mediated by Huntingtin Exon1 Protein Fragment

Distinguishing aggregate formation and aggregate clearance using cell-based assays

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