Soluble expanded PABPN1 promotes cell death in oculopharyngeal muscular dystrophy

Messaed, Christiane; Abu-Baker, Aida; Rochefort, Daniel; Laganière, Janet; Brais, Bernard; Rouleau, Guy

doi:10.1016/j.nbd.2007.02.004

Cited by 38 publications

(28 citation statements)

References 53 publications

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“…This theory could account for the susceptibility of muscles associated with OPMD, since these highly metabolically active cells may be more sensitive to perturbations in cellular machinery. Our further observation that the formation of protein aggregates does not entirely correlate with cell death [22] have contradicted the theory of inclusion body toxicity, adding to the increasing evidence suggesting that they might instead serve a protective role within cells. It is now generally accepted that the toxic species are smaller, less visible micro-aggregates [61].…”

Section: Adapt-232 and Usp14 Inhibitor (Chaperones And Ubiquitinprotecontrasting

confidence: 71%

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Current targeted therapeutic strategies for oculopharyngeal muscular dystrophy: from pharmacological to RNA replacement and gene editing therapies

Abu-Baker¹,

Kharma²,

Néri³

et al. 2016

IJCNMH

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Oculopharyngeal muscular dystrophy (OPMD) is a midlife onset hereditary disease affecting skeletal muscles. It is characterized by progressive eyelid drooping, swallowing difficulties and proximal limb weakness. The distinct pathological hallmark of OPMD is the presence of filamentous intranuclear inclusions (INI) in patient's skeletal muscle cells. OPMD is caused by a mutation in the poly (A) binding protein nuclear 1 protein (PABPN1) gene, located on chromosome 14q. The normal PABPN1 gene has a (GCG)6 repeat encoding a polyalanine stretch at the 5' end, while in OPMD patients this repeat is expanded to (GCG)8-13. Currently there is no effective treatment for OPMD. In this review, we discuss our current treatment strategies for OPMD. We present three experimental therapeutic approaches: pharmacological, RNA replacement, and gene editing. Our scientific findings could ultimately lead to an effective therapy for OPMD patients.

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Section: Adapt-232 and Usp14 Inhibitor (Chaperones And Ubiquitinprotecontrasting

confidence: 71%

“…Our initial hypothesis was that expanded polyalanine tract of exp PABPN1 forms β-pleated sheets that give rise to toxic INI. As our work progresses, we are discovering that soluble exp PABPN1 may be the most critical species for toxicity [22].…”

Section: Introductionmentioning

confidence: 99%

Current targeted therapeutic strategies for oculopharyngeal muscular dystrophy: from pharmacological to RNA replacement and gene editing therapies

Abu-Baker¹,

Kharma²,

Néri³

et al. 2016

IJCNMH

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“…The a-helix domain is essential for the activity of poly(A)polymerase [5,15] and deletion of two glutamate residues (Glu131 and Glu132) from the a-helix domain of PABPN1, both of which were shown to be involved in the binding with 3F5, results in an increased proportion of soluble PABPN1 [16]. Similar results were also obtained when deletion of the entire a-helix domain or substitution of Leu136 prevented formation of insoluble PABPN1 deposits [5].…”

Section: Discussionsupporting

confidence: 57%

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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“…For example, the human muscle degenerative disease oculopharyngeal muscular dystrophy (OPMD) is caused by a GCG repeat expansion in the HsnPABP2 gene. This GCG expansion results in an expanded polyalanine tract in the HsnPABP2 protein (22). HsnPABP2 proteins with polyalanine expansions aggregate, and in muscle cells, these aggregates contribute to the disease pathology of OPMD.…”

Section: Discussionmentioning

confidence: 99%

Structural basis for RNA recognition by a type II poly(A)-binding protein

Song

McGivern²,

Nichols³

et al. 2008

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

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We identified a functional domain (XlePABP2-TRP) of Xenopus laevis embryonic type II poly(A)-binding protein (XlePABP2). The NMR structure of XlePABP2-TRP revealed that the protein is a homodimer formed by the antiparallel association of ␤-strands from the single RNA recognition motif (RRM) domain of each subunit. In each subunit of the homodimer, the canonical RNA recognition site is occluded by a polyproline motif. Upon poly(A) binding, XlePABP2-TRP undergoes a dimer-monomer transition that removes the polyproline motif from the RNA recognition site and allows it to be replaced by the adenosine nucleotides of poly(A). Our results provide high-resolution structural information concerning type II PABPs and an example of a single RRM domain protein that transitions from a homodimer to a monomer upon RNA binding. These findings advance our understanding of RRM domain regulation, poly(A) recognition, and are relevant to understanding how type II PABPs function in mRNA processing and human disease.

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Soluble expanded PABPN1 promotes cell death in oculopharyngeal muscular dystrophy

Cited by 38 publications

References 53 publications

Current targeted therapeutic strategies for oculopharyngeal muscular dystrophy: from pharmacological to RNA replacement and gene editing therapies

Current targeted therapeutic strategies for oculopharyngeal muscular dystrophy: from pharmacological to RNA replacement and gene editing therapies

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

Structural basis for RNA recognition by a type II poly(A)-binding protein

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