Abstract
The prospective increase in life expectancy will be accompanied by a rise in the number of elderly people who suffer from ill health caused by old age. Many diseases caused by aging are protein misfolding diseases. The molecular mechanisms underlying these disorders receive constant scientific interest. In addition to old age, mutations also cause congenital protein misfolding disorders. Chorea Huntington, one of the most well-known examples, is caused by triplet extensions that can lead to more than 100 glutamines in the N-terminal region of huntingtin, accompanied by huntingtin aggregation. So far, nine disease-associated triplet extensions have also been described for alanine codons. The extensions lead primarily to skeletal malformations. Eight of these proteins represent transcription factors, while the nuclear poly-adenylate binding protein 1, PABPN1, is an RNA binding protein. Additional alanines in PABPN1 lead to the disease oculopharyngeal muscular dystrophy (OPMD). The alanine extension affects the N-terminal domain of the protein, which has been shown to lack tertiary contacts. Biochemical analyses of the N-terminal domain revealed an alanine-dependent fibril formation. However, fibril formation of full-length protein did not recapitulate the findings of the N-terminal domain. Fibril formation of intact PABPN1 was independent of the alanine segment, and the fibrils displayed biochemical properties that were completely different from those of the N-terminal domain. Although intranuclear inclusions have been shown to represent the histochemical hallmark of OPMD, their role in pathogenesis is currently unclear. Several cell culture and animal models have been generated to study the molecular processes involved in OPMD. These studies revealed a number of promising future therapeutic strategies that could one day improve the quality of life for the patients.
We thank the Deutsche Forschungsgemeinschaft for funding through the SFB610. We wish to thank Jay Goodman for polishing the English.
References
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Articles in the same Issue
- Masthead
- Masthead
- Guest Editorial
- Highlight: Protein states with cell biological and medicinal relevance
- HIGHLIGHT: PROTEIN STATES WITH CELL BIOLOGICAL AND MEDICAL RELEVANCE
- Towards improved receptor targeting: anterograde transport, internalization and postendocytic trafficking of neuropeptide Y receptors
- Progress in demystification of adhesion G protein-coupled receptors
- The unresolved puzzle why alanine extensions cause disease
- Molecular function of the prolyl cis/trans isomerase and metallochaperone SlyD
- Structure and allosteric regulation of eukaryotic 6-phosphofructokinases
- Polyionic and cysteine-containing fusion peptides as versatile protein tags
- p0071/PKP4, a multifunctional protein coordinating cell adhesion with cytoskeletal organization
- Lysine-specific histone demethylase LSD1 and the dynamic control of chromatin
- Methylation of the nuclear poly(A)-binding protein by type I protein arginine methyltransferases – how and why
- Oxidative in vitro folding of a cysteine deficient variant of the G protein-coupled neuropeptide Y receptor type 2 improves stability at high concentration
- Identification of prolyl oligopeptidase as a cyclosporine-sensitive protease by screening of mouse liver extracts
- In vitro maturation of Drosophila melanogaster Spätzle protein with refolded Easter reveals a novel cleavage site within the prodomain
- Subcellular localization and RNP formation of IGF2BPs (IGF2 mRNA-binding proteins) is modulated by distinct RNA-binding domains
- High level expression of the Drosophila Toll receptor ectodomain and crystallization of its complex with the morphogen Spätzle
Articles in the same Issue
- Masthead
- Masthead
- Guest Editorial
- Highlight: Protein states with cell biological and medicinal relevance
- HIGHLIGHT: PROTEIN STATES WITH CELL BIOLOGICAL AND MEDICAL RELEVANCE
- Towards improved receptor targeting: anterograde transport, internalization and postendocytic trafficking of neuropeptide Y receptors
- Progress in demystification of adhesion G protein-coupled receptors
- The unresolved puzzle why alanine extensions cause disease
- Molecular function of the prolyl cis/trans isomerase and metallochaperone SlyD
- Structure and allosteric regulation of eukaryotic 6-phosphofructokinases
- Polyionic and cysteine-containing fusion peptides as versatile protein tags
- p0071/PKP4, a multifunctional protein coordinating cell adhesion with cytoskeletal organization
- Lysine-specific histone demethylase LSD1 and the dynamic control of chromatin
- Methylation of the nuclear poly(A)-binding protein by type I protein arginine methyltransferases – how and why
- Oxidative in vitro folding of a cysteine deficient variant of the G protein-coupled neuropeptide Y receptor type 2 improves stability at high concentration
- Identification of prolyl oligopeptidase as a cyclosporine-sensitive protease by screening of mouse liver extracts
- In vitro maturation of Drosophila melanogaster Spätzle protein with refolded Easter reveals a novel cleavage site within the prodomain
- Subcellular localization and RNP formation of IGF2BPs (IGF2 mRNA-binding proteins) is modulated by distinct RNA-binding domains
- High level expression of the Drosophila Toll receptor ectodomain and crystallization of its complex with the morphogen Spätzle