CHIP targets toxic alpha-Synuclein oligomers for degradation.
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.
Tetzlaff
Julie E
JE
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Putcha
Preeti
P
Outeiro
Tiago F
TF
Ivanov
Alexander
A
Berezovska
Oksana
O
Hyman
Bradley T
BT
McLean
Pamela J
PJ
D045744:Cell Line, Tumor; D003902:Detergents / Q000494:pharmacology; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000737:chemistry; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry; D006801:Humans; D008856:Microscopy, Fluorescence; D008970:Molecular Weight; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013347:Subcellular Fractions / Q000737:chemistry; D013696:Temperature; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
D003902:Detergents; D018840:HSP70 Heat-Shock Proteins; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases