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Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of autosomal-dominant Parkinson’s disease (PD). The second known autosomal-dominant PD gene (SNCA) encodes α-synuclein, which is deposited in Lewy bodies, the neuropathological hallmark of PD. LRRK2 contains a kinase domain with homology to mitogen-activated protein kinase kinase kinases (MAPKKKs) and its activity has been suggested to be a key factor in LRRK2-associated PD. Here we investigated the role of LRRK2 in signal transduction pathways to identify putative PD-relevant downstream targets. Over-expression of wild-type [wt]LRRK2 in human embryonic kidney HEK293 cells selectively activated the extracellular signal-regulated kinase (ERK) module. PD-associated mutants G2019S and R1441C, but not kinase-dead LRRK2, induced ERK phosphorylation to the same extent as [wt]LRRK2, indicating that this effect is kinase-dependent. However, ERK activation by mutant R1441C and G2019S was significantly slower than that for [wt]LRRK2, despite similar levels of expression. Furthermore, induction of the ERK module by LRRK2 was associated to a small but significant induction of SNCA, which was suppressed by treatment with the selective MAPK/ERK kinase inhibitor U0126. This pathway linking the two dominant PD genes LRRK2 and SNCA may offer an interesting target for drug therapy in both familial and sporadic disease.
LRRK2, Mitogen-activated protein kinases, ERK, α-Synuclein, Parkinson’s disease
Leucine-rich repeat kinase 2 induces α-synuclein expression via the extracellular signal-regulated kinase pathway
Iria Carballo-Carbajal,a,1 Susanne Weber-Endress,a Giorgio Rovelli,b Diane Chan,c Benjamin Wolozin,c Christian L. Klein,a Nadja Patenge,a,2 Thomas Gasser,a and Philipp J. Kahlea,*
2011 Aug 28.
The title compound, C26H25BrN2, is isomorphous with the chloro derivative [2-(4-chlorophenyl)-1-pentyl-4,5-diphenyl-1H-imidazole; Mohamed et al. (2013 ▶). Acta Cryst. E69, o846-o847]. The two phenyl rings and the 4-bromophenyl ring are oriented at dihedral angles of 30.1 (2), 64.3 (3) and 42.0 (2)°, respectively, with respect to the imidazole ring. In the crystal, molecules stack in columns along the b-axis direction, however, there are no significant intermolecular interactions present.
Shaaban K. Mohamed,a,b Mehmet Akkurt,c Kuldip Singh,d Adel A. Marzouk,e and Mustafa R. Albayatif,*
2013 Sep 1;
Different from previous researches which mostly focused on linear response control of seismically excited high-rise buildings, this study aims to control nonlinear seismic response of high-rise buildings. To this end, a semi-active control strategy, in which H∞ control algorithm is used and magneto-rheological dampers are employed for an actuator, is presented to suppress the nonlinear vibration. In this strategy, a modified Kalman-Bucy observer which is suitable for the proposed semi-active strategy is developed to obtain the state vector from the measured semi-active control force and acceleration feedback, taking into account of the effects of nonlinearity, disturbance and uncertainty of controlled system parameters by the observed nonlinear accelerations. Then, the proposed semi-active H∞ control strategy is applied to the ASCE 20-story benchmark building when subjected to earthquake excitation and compared with the other control approaches by some control criteria. It is indicated that the proposed semi-active H∞ control strategy provides much better control performances by comparison with the semi-active MPC and Clipped-LQG control approaches, and can reduce nonlinear seismic response and minimize the damage in the buildings. Besides, it enhances the reliability of the control performance when compared with the active control strategy. Thus, the proposed semi-active H∞ control strategy is suitable for suppressing the nonlinear vibration of high-rise buildings.
Semi-active strategy, H∞ control algorithm, High-rise building, Nonlinear seismic response, Kalman-Bucy estimator
A semi-active H∞ control strategy with application to the vibration suppression of nonlinear high-rise building under earthquake excitations
Guiyun Yan,corresponding author Fuquan Chen, and Yingxiong Wu