FK506 binding protein 12 differentially accelerates fibril formation of wild type alpha-synuclein and its clinical mutants A30P or A53T.
Aggregation of alpha-synuclein (alpha-SYN) plays a key role in Parkinson's disease. We have previously shown that aggregation of alpha-SYN in vitro is accelerated by addition of FK506 binding proteins (FKBP) and that this effect can be counteracted by FK506, a specific inhibitor of these enzymes. In this paper, we investigated in detail the effect of FKBP12 on early aggregation and on fibril formation of wild-type, A53T and A30P alpha-SYN. FKBP12 has a much smaller effect on the fibril formation of these two clinical mutants alpha-SYN. Using an inactive enzyme, we were able to discriminate between catalytic and non-catalytic effects that differentially influence the two processes. A model explaining non-linear concentration dependencies is proposed.
Gerard
Melanie
M
Laboratory of Biomolecular Dynamics, K. U. Leuven, Flanders, Belgium.
Debyser
Zeger
Z
Desender
Linda
L
Baert
Johan
J
Brandt
Inger
I
Baekelandt
Veerle
V
Engelborghs
Yves
Y
D019943:Amino Acid Substitution; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020134:Catalytic Domain / Q000235:genetics; D045744:Cell Line, Tumor; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017711:Nonlinear Dynamics; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016559:Tacrolimus / Q000494:pharmacology; D022061:Tacrolimus Binding Protein 1A / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D013997:Time Factors; D051844:alpha-Synuclein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D007166:Immunosuppressive Agents; D051844:alpha-Synuclein; D022061:Tacrolimus Binding Protein 1A; D016559:Tacrolimus