TY  - JOUR
A1  - Kohl, S.
A1  - Gruendler, T. O. J.
A1  - Huys, D.
A1  - Sildatke, E.
A1  - Dembek, T. A.
A1  - Hellmich, M.
A1  - Vorderwulbecke, M.
A1  - Timmermann, L.
A1  - Ahmari, S. E.
A1  - Klosterkoetter, J.
A1  - Jessen, F.
A1  - Sturm, V.
A1  - Visser-Vandewalle, V.
A1  - Kuhn, J.
T1  - Effects of deep brain stimulation on prepulse inhibition in obsessive-compulsive disorder
JF  - Translational Psychiatry
N2  - Owing to a high response rate, deep brain stimulation (DBS) of the ventral striatal area has been approved for treatment-refractory obsessive-compulsive disorder (tr-OCD). Many basic issues regarding DBS for tr-OCD are still not understood, in particular, the mechanisms of action and the origin of side effects. We measured prepulse inhibition (PPI) in treatment-refractory OCD patients undergoing DBS of the nucleus accumbens (NAcc) and matched controls. As PPI has been used in animal DBS studies, it is highly suitable for translational research. Eight patients receiving DBS, eight patients with pharmacological treatment and eight age-matched healthy controls participated in our study. PPI was measured twice in the DBS group: one session with the stimulator switched on and one session with the stimulator switched off. OCD patients in the pharmacologic group took part in a single session. Controls were tested twice, to ensure stability of data. Statistical analysis revealed significant differences between controls and (1) patients with pharmacological treatment and (2) OCD DBS patients when the stimulation was switched off. Switching the stimulator on led to an increase in PPI at a stimulus-onset asynchrony of 200 ms. There was no significant difference in PPI between OCD patients being stimulated and the control group. This study shows that NAcc-DBS leads to an increase in PPI in tr-OCD patients towards a level seen in healthy controls. Assuming that PPI impairments partially reflect the neurobiological substrates of OCD, our results show that DBS of the NAcc may improve sensorimotor gating via correction of dysfunctional neural substrates. Bearing in mind that PPI is based on a complex and multilayered network, our data confirm that DBS most likely takes effect via network modulation.
KW  - nucleus
KW  - serotonin
KW  - schizophrenia
KW  - dopamine
KW  - double-blind
KW  - psychiatric disorders
KW  - in vivo
KW  - acoustic startle
KW  - reflex
KW  - modulation
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-138300
VL  - 5
IS  - e675
ER  - 
TY  - JOUR
A1  - Heiby, Julia C.
A1  - Goretzki, Benedikt
A1  - Johnson, Christopher M.
A1  - Hellmich, Ute A.
A1  - Neuweiler, Hannes
T1  - Methionine in a protein hydrophobic core drives tight interactions required for assembly of spider silk
JF  - Nature Communications
N2  - Web spiders connect silk proteins, so-called spidroins, into fibers of extraordinary toughness. The spidroin N-terminal domain (NTD) plays a pivotal role in this process: it polymerizes spidroins through a complex mechanism of dimerization. Here we analyze sequences of spidroin NTDs and find an unusually high content of the amino acid methionine. We simultaneously mutate all methionines present in the hydrophobic core of a spidroin NTD from a nursery web spider’s dragline silk to leucine. The mutated NTD is strongly stabilized and folds at the theoretical speed limit. The structure of the mutant is preserved, yet its ability to dimerize is substantially impaired. We find that side chains of core methionines serve to mobilize the fold, which can thereby access various conformations and adapt the association interface for tight binding. Methionine in a hydrophobic core equips a protein with the capacity to dynamically change shape and thus to optimize its function.
KW  - Circular dichroism
KW  - Fluorescence spectroscopy
KW  - Protein folding
KW  - Solution-state NMR
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202539
VL  - 10
ER  -