In vivo aggregation properties of the nuclear poly(A)-binding protein PABPN1

Tavanez, João Paulo; Calado, Patrícia; Braga, Juan C.; Lafarga, Miguel; Carmo‐Fonseca, Maria

doi:10.1261/rna.7217105

Cited by 66 publications

(78 citation statements)

References 53 publications

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“…Similar results were also obtained when deletion of the entire a-helix domain or substitution of Leu136 prevented formation of insoluble PABPN1 deposits [5]. In Drosophila, flies co-expressing mutant PABPN1 and 3F5 showed reduced aggregate sizes and dispersed inclusion formation compared to flies only expressing mutant PABPN1 [7].…”

Section: Discussionsupporting

confidence: 72%

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Structural basis for a PABPN1 aggregation‐preventing antibody fragment in OPMD

Impagliazzo¹,

Tepper²,

Verrips³

et al. 2010

FEBS Letters

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a b s t r a c tOculopharyngeal muscular dystrophy is caused by small alanine expansions in polyadenylate binding protein nuclear 1 (PABPN1) protein resulting in its intranuclear accumulation in skeletal muscle. 3F5 llama antibody specifically interferes with the PABPN1 aggregation process in vitro and in vivo. To understand the structural basis for its epitope recognition we mapped the binding interface of 3F5 with PABPN1 and provide a structural model of the 3F5-PABPN1 complex. We show that 3F5 complementarity determining regions create a cavity in which PABPN1 a-helix domain resides by involving critical residues previously implicated in the aggregation process. These results may increase our understanding of the PABPN1 aggregation mechanism and the therapeutic potential of 3F5.

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Section: Discussionsupporting

confidence: 72%

“…Huntington's disease, belongs to a group of disorders, which is associated with the accumulation of misfolded protein [4]. A characteristic feature of OPMD is therefore the presence of filamentous intranuclear inclusions in skeletal muscle fibers [5].…”

Section: Introductionmentioning

confidence: 99%

Structural basis for a PABPN1 aggregation‐preventing antibody fragment in OPMD

Impagliazzo¹,

Tepper²,

Verrips³

et al. 2010

FEBS Letters

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“…16 Also, in our cell model, PABPN1-FLAG colocalized with SC35 in unfused cells that were incubated in fusion conditions for only 1 day (Figure 2A). This further indicates that FLAG tagging did not disrupt the nuclear localization of the PABPN1 transgene products.…”

Section: Expression Of Wt or Exppabpn1 In Mouse Myotube Cultures At Lmentioning

confidence: 62%

“…13,14 In contrast to INI in OPMD myofibers, inclusions of the WT protein are not associated with disease. [15][16][17] The mechanisms by which expPABPN1 causes muscle weakness are not well understood.…”

mentioning

confidence: 99%

Modeling Oculopharyngeal Muscular Dystrophy in Myotube Cultures Reveals Reduced Accumulation of Soluble Mutant PABPN1 Protein

Raz

Routledge

Venema

et al. 2011

The American Journal of Pathology

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Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disease caused by an alanine tract expansion mutation in poly(A) binding protein nuclear 1 (expPABPN1). To model OPMD in a myogenic and physiological context, we generated mouse myoblast cell clones stably expressing either human wild type (WT) or expPABPN1 at low levels. Transgene expression is induced on myotube differentiation and results in formation of insoluble nuclear PABPN1 aggregates that are similar to those observed in patients with OPMD. Quantitative analysis of PABPN1 in myotube cultures revealed that expPABPN1 accumulation and aggregation is greater than that of the WT protein. We found that aggregation of expPABPN1 is more affected than WT PABPN1 by inhibition of proteasome activity. Consistent with this, in myotube cultures expressing expPABPN1, deregulation of the proteasome was identified as the most significantly perturbed pathway. Differences in the accumulation of soluble WT and expPABPN1 were consistent with differences in ubiquitination and rate of protein turnover. This study demonstrates, for the first time to our knowledge, that, in myotubes, the ratio of soluble/insoluble expPABPN1 is significantly lower compared with that of the WT protein. We suggest that this difference can contribute to muscle weakness in OPMD.

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“…The wild type PABPN1 was shown by immuno fluorescent microscopy to colocalize with the splicing factor SC35 and the nuclear matrix associated protein PML while the mutant PABPN1 did not (Messaed et. al., 2007;Tavanez et. al., 2005).…”

Section: Protein Aggregates and Cell Deathmentioning

confidence: 99%