TY  - JOUR
AU  - Wördehoff, Michael M.
AU  - Bannach, Oliver
AU  - Shaykhalishahi, Hamed
AU  - Kulawik, Andreas
AU  - Schiefer, Stephanie
AU  - Willbold, Dieter
AU  - Hoyer, Wolfgang
AU  - Birkmann, Eva
TI  - Single Fibril Growth Kinetics of α-Synuclein
JO  - Journal of molecular biology
VL  - 427
IS  - 6 B
SN  - 0022-2836
CY  - Amsterdam [u.a.]
PB  - Elsevier
M1  - FZJ-2015-05195
SP  - 1428 - 1435
PY  - 2015
AB  - Neurodegenerative disorders associated with protein misfolding are fatal diseases that are caused by fibrillation of endogenous proteins such as α-synuclein (α-syn) in Parkinson's disease (PD) or amyloid-β in Alzheimer's disease. Fibrils of α-syn are a major pathological hallmark of PD and certain aggregation intermediates are postulated to cause synaptic failure and cell death of dopaminergic neurons in the substantia nigra. For the development of therapeutic approaches, the mechanistic understanding of the fibrillation process is essential. Here we report real-time observation of α-syn fibril elongation on a glass surface, imaged by total internal reflection fluorescence microscopy using thioflavin T fluorescence. Fibrillation on the glass surface occurred in the same time frame and yielded fibrils of similar length as fibrillation in solution. Time-resolved imaging of fibrillation on a single fibril level indicated that α-syn fibril elongation follows a stop-and-go mechanism; that is, fibrils either extend at a homogenous growth rate or stop to grow for variable time intervals. The fibril growth kinetics were compatible with a model featuring two states, a growth state and a stop state, which were approximately isoenergetic and interconverted with rate constants of ~ 1.5 × 10− 4 s− 1. In the growth state, α-syn monomers were incorporated into the fibril with a rate constant of 8.6 × 103 M− 1 s− 1. Fibril elongation of α-syn is slow compared to other amyloidogenic proteins.
LB  - PUB:(DE-HGF)16
UR  - <Go to ISI:>//WOS:000351798700016
C6  - pmid:25659910
DO  - DOI:10.1016/j.jmb.2015.01.020
UR  - https://juser.fz-juelich.de/record/203194
ER  -