HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Polyglutamine expansion alters the dynamics and molecular architecture of aggregates in dentatorubropallidoluysian atrophy.

Abstract
Preferential accumulation of mutant proteins in the nucleus has been suggested to be the molecular culprit that confers cellular toxicity in the neurodegenerative disorders caused by polyglutamine (polyQ) expansion. Here, we use dynamic imaging approaches, orthogonal cross-seeding, and composition analysis to examine the dynamics and structure of nuclear and cytoplasmic inclusions of atrophin-1, implicated in dentatorubropallidoluysian atrophy, a polyQ-based disease with complex clinical features. Our results reveal a large heterogeneity in the dynamics of the nuclear inclusions compared with the compact and immobile cytoplasmic aggregates. At least two types of inclusions of expanded atrophin-1 with different mobility of the molecular species and ability to exchange with the surrounding monomer pool coexist in the nucleus. Intriguingly, the enrichment of nuclear inclusions with slow dynamics parallels changes in the aggregate core architecture that are dominated by the polyQ stretch. We propose that the observed complexity in the dynamics of the nuclear inclusions provides a molecular explanation for the enhanced cellular toxicity of the nuclear aggregates in polyQ-based neurodegeneration.
AuthorsJustyna Hinz, Lothar Lehnhardt, Silke Zakrzewski, Gong Zhang, Zoya Ignatova
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 3 Pg. 2068-78 (Jan 13 2012) ISSN: 1083-351X [Electronic] United States
PMID22134925 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Multiprotein Complexes
  • Nerve Tissue Proteins
  • Peptides
  • atrophin-1
  • polyglutamine
Topics
  • Animals
  • Atrophy (genetics, metabolism, pathology)
  • Cell Line
  • Cytoplasm (genetics, metabolism, pathology)
  • Heredodegenerative Disorders, Nervous System (genetics, metabolism, pathology)
  • Humans
  • Mice
  • Multiprotein Complexes (genetics, metabolism)
  • Nerve Tissue Proteins (genetics, metabolism)
  • Peptides (genetics, metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: