Prefoldin Protects Neuronal Cells from Polyglutamine Toxicity by Preventing Aggregation Formation
| Autor: | Hiroyoshi Ariga, Mizuo Maeda, Hideki Muto, Akira Kitamura, Makoto Miyazawa, Karin Sörgjerd, Tamotsu Zako, Yoshinori Itoo, Akira Abe, Hiroshi Kubota, Takashi Momoi, Sanae M.M. Iguchi-Ariga, Naofumi Terada, Masataka Kinjo, Erika Tashiro, Hirotake Kitaura |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Programmed cell death Huntingtin Repressor Nerve Tissue Proteins Biology Protein aggregation Biochemistry Cell Line Tumor mental disorders Huntingtin Protein medicine Humans Molecular Biology Neurons Gene knockdown Cell Death Neurodegeneration Molecular Bases of Disease Cell Biology medicine.disease Molecular biology nervous system diseases Prefoldin Cell biology Repressor Proteins Solubility nervous system Peptides Molecular Chaperones |
| Zdroj: | Journal of Biological Chemistry. 288(27):19958-19972 |
| ISSN: | 0021-9258 |
| Popis: | Huntington disease is caused by cell death after the expansion of polyglutamine (polyQ) tracts longer than ∼40 repeats encoded by exon 1 of the huntingtin (HTT) gene. Prefoldin is a molecular chaperone composed of six subunits, PFD1–6, and prevents misfolding of newly synthesized nascent polypeptides. In this study, we found that knockdown of PFD2 and PFD5 disrupted prefoldin formation in HTT-expressing cells, resulting in accumulation of aggregates of a pathogenic form of HTT and in induction of cell death. Dead cells, however, did not contain inclusions of HTT, and analysis by a fluorescence correlation spectroscopy indicated that knockdown of PFD2 and PFD5 also increased the size of soluble oligomers of pathogenic HTT in cells. In vitro single molecule observation demonstrated that prefoldin suppressed HTT aggregation at the small oligomer (dimer to tetramer) stage. These results indicate that prefoldin inhibits elongation of large oligomers of pathogenic Htt, thereby inhibiting subsequent inclusion formation, and suggest that soluble oligomers of polyQ-expanded HTT are more toxic than are inclusion to cells. Background: Prefoldin, a molecular chaperone composed of six subunits, prevents misfolding of newly synthesized nascent polypeptides. Results: Prefoldin inhibited aggregation of pathogenic Huntingtin and subsequent cell death. Conclusion: Prefoldin suppressed Huntingtin aggregation at the small oligomer stage. Significance: Prefoldin plays a role in preventing protein aggregation in Huntington disease. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|