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CHIP targets toxic alpha-Synuclein oligomers for degradation. J Biol Chem 2008 Jun 27;283(26):17962-8

Date

04/26/2008

Pubmed ID

18436529

Pubmed Central ID

PMC2936239

DOI

10.1074/jbc.M802283200

Scopus ID

2-s2.0-49649125680 (requires institutional sign-in at Scopus site)   146 Citations

Abstract

alpha-Synuclein (alphaSyn) can self-associate, forming oligomers, fibrils, and Lewy bodies, the pathological hallmark of Parkinson disease. Current dogma suggests that oligomeric alphaSyn intermediates may represent the most toxic alphaSyn species. Here, we studied the effect of a potent molecular chaperone, CHIP (carboxyl terminus of Hsp70-interacting protein), on alphaSyn oligomerization using a novel bimolecular fluorescence complementation assay. CHIP is a multidomain chaperone, utilizing both a tetratricopeptide/Hsp70 binding domain and a U-box/ubiquitin ligase domain to differentially impact the fate of misfolded proteins. In the current study, we found that co-expression of CHIP selectively reduced alphaSyn oligomerization and toxicity in a tetratricopeptide domain-dependent, U-box-independent manner by specifically degrading toxic alphaSyn oligomers. We conclude that CHIP preferentially recognizes and mediates degradation of toxic, oligomeric forms of alphaSyn. Further elucidation of the mechanisms of CHIP-induced degradation of oligomeric alphaSyn may contribute to the successful development of drug therapies that target oligomeric alphaSyn by mimicking or enhancing the powerful effects of CHIP.

Author List

Tetzlaff JE, Putcha P, Outeiro TF, Ivanov A, Berezovska O, Hyman BT, McLean PJ

Author

Julie Tetzlaff PhD Associate Dean, Associate Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Cell Line, Tumor
Detergents
Flow Cytometry
Green Fluorescent Proteins
HSP70 Heat-Shock Proteins
Humans
Microscopy, Fluorescence
Molecular Weight
Protein Binding
Protein Structure, Tertiary
Subcellular Fractions
Temperature
Transfection
Ubiquitin-Protein Ligases
alpha-Synuclein