TY  - JOUR
A1  - Schul, Daniela
A1  - Schmitt, Alexandra
A1  - Regneri, Janine
A1  - Schartl, Manfred
A1  - Wagner, Toni Ulrich
T1  - Bursted BMP Triggered Receptor Kinase Activity Drives Smad1 Mediated Long-Term Target Gene Oscillation in c2c12 Cells
JF  - PLoS ONE
N2  - Bone Morphogenetic Proteins (BMPs) are important growth factors that regulate many cellular processes. During embryogenesis they act as morphogens and play a critical role during organ development. They influence cell fates via concentration-gradients in the embryos where cells transduce this extracellular information into gene expression profiles and cell fate decisions. How receiving cells decode and quantify BMP2/4 signals is hardly understood. There is little data on the quantitative relationships between signal input, transducing molecules, their states and location, and ultimately their ability to integrate graded systemic inputs and generate qualitative responses. Understanding this signaling network on a quantitative level should be considered a prerequisite for efficient pathway modulation, as the BMP pathway is a prime target for therapeutic invention. Hence, we quantified the spatial distribution of the main signal transducer of the BMP2/4 pathway in response to different types and levels of stimuli in c2c12 cells. We found that the subcellular localization of Smad1 is independent of ligand concentration. In contrast, Smad1 phosphorylation levels relate proportionally to BMP2 ligand concentrations and they are entirely located in the nucleus. Interestingly, we found that BMP2 stimulates target gene expression in non-linear, wave-like forms. Amplitudes showed a clear concentration-dependency, for sustained and transient stimulation. We found that even burst-stimulation triggers gene-expression wave-like modulations that are detectable for at least 30 h. Finally, we show here that target gene expression oscillations depend on receptor kinase activity, as the kinase drives further expression pulses without receptor reactivation and the target gene expression breaks off after inhibitor treatment in c2c12 cells.
KW  - gene expression
KW  - BMP signaling
KW  - SMAD signaling
KW  - genetic oscillators
KW  - cell fusion
KW  - DNA-binding proteins
KW  - luciferase
KW  - kinase inhibitors
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130131
VL  - 8
IS  - 4
ER  - 
TY  - JOUR
A1  - Kuzkina, Anastasia
A1  - Bargar, Connor
A1  - Schmitt, Daniela
A1  - Rößle, Jonas
A1  - Wang, Wen
A1  - Schubert, Anna-Lena
A1  - Tatsuoka, Curtis
A1  - Gunzler, Steven A.
A1  - Zou, Wen-Quan
A1  - Volkmann, Jens
A1  - Sommer, Claudia
A1  - Doppler, Kathrin
A1  - Chen, Shu G.
T1  - Diagnostic value of skin RT-QuIC in Parkinson's disease: a two-laboratory study
JF  - NPJ Parkinson's Disease
N2  - Skin alpha-synuclein deposition is considered a potential biomarker for Parkinson's disease (PD). Real-time quaking-induced conversion (RT-QuIC) is a novel, ultrasensitive, and efficient seeding assay that enables the detection of minute amounts of alpha-synuclein aggregates. We aimed to determine the diagnostic accuracy, reliability, and reproducibility of alpha-synuclein RT-QuIC assay of skin biopsy for diagnosing PD and to explore its correlation with clinical markers of PD in a two-center inter-laboratory comparison study. Patients with clinically diagnosed PD (n = 34), as well as control subjects (n = 30), underwent skin punch biopsy at multiple sites (neck, lower back, thigh, and lower leg). The skin biopsy samples (198 in total) were divided in half to be analyzed by RT-QuIC assay in two independent laboratories. The a-synuclein RT-QuIC assay of multiple skin biopsies supported the clinical diagnosis of PD with a diagnostic accuracy of 88.9% and showed a high degree of inter-rater agreement between the two laboratories (92.2%). Higher alpha-synuclein seeding activity in RT-QuIC was shown in patients with longer disease duration and more advanced disease stage and correlated with the presence of REM sleep behavior disorder, cognitive impairment, and constipation. The alpha-synuclein RT-QuIC assay of minimally invasive skin punch biopsy is a reliable and reproducible biomarker for Parkinson's disease. Moreover, alpha-synuclein RT-QuIC seeding activity in the skin may serve as a potential indicator of progression as it correlates with the disease stage and certain non-motor symptoms.
KW  - diagnostic markers
KW  - Parkinson's disease
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260451
VL  - 7
IS  - 1
ER  -