Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations

​Leucine-rich repeat kinase 2 (​LRRK2) mutations are the most common genetic cause of Parkinson’s disease. ​LRRK2 is a multifunctional protein affecting many cellular processes and has been described to bind microtubules. Defective microtubule-based axonal transport is hypothesized to contribute to Parkinson’s disease, but whether ​LRRK2 mutations affect this process to mediate pathogenesis is not known. Here we find that ​LRRK2 containing pathogenic Roc-COR domain mutations (R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transport in primary neurons and in Drosophila, causing locomotor deficits in vivo. In vitro, increasing microtubule acetylation using deacetylase inhibitors or the tubulin acetylase ​αTAT1 prevents association of mutant ​LRRK2 with microtubules, and the deacetylase inhibitor ​trichostatin A (​TSA) restores axonal transport. In vivo knockdown of the deacetylases ​HDAC6 and ​Sirt2, or administration of ​TSA rescues both axonal transport and locomotor behavior. Thus, this study reveals a pathogenic mechanism and a potential intervention for Parkinson’s disease

A Bacterial Acetyltransferase Destroys Plant Microtubule Networks and Blocks Secretion

The eukaryotic cytoskeleton is essential for structural support and intracellular transport, and is therefore a common target of animal pathogens. However, no phytopathogenic effector has yet been demonstrated to specifically target the plant cytoskeleton. Here we show that the Pseudomonas syringae type III secreted effector HopZ1a interacts with tubulin and polymerized microtubules. We demonstrate that HopZ1a is an acetyltransferase activated by the eukaryotic co-factor phytic acid. Activated HopZ1a acetylates itself and tubulin. The conserved autoacetylation site of the YopJ / HopZ superfamily, K289, plays a critical role in both the avirulence and virulence function of HopZ1a. Furthermore, HopZ1a requires its acetyltransferase activity to cause a dramatic decrease in Arabidopsis thaliana microtubule networks, disrupt the plant secretory pathway and suppress cell wall-mediated defense. Together, this study supports the hypothesis that HopZ1a promotes virulence through cytoskeletal and secretory disruption

Catastrophic Drop Breakup in Electric Field

We report novel observations revealing the catastrophic breakup of water drops containing surfactant molecules, which are suspended in oil and subjected to an electric field of strength similar to 10(5) V/m. The observed breakup was distinctly different from the gradual end pinch-off or tip-streaming modes reported earlier in the literature. There was no observable characteristic deformation of the drop prior to breakup. The time scales involved in the breakup and the resultant droplet sizes were much smaller in the phenomenon observed by us. We hypothesize that this mode of drop breakup is obtained by the combined effect of an external electric field that imposes tensile stresses on the surface of the drop, and characteristic stress-strain behavior for tensile deformation exhibited by the liquid drop in the presence of a suitable surfactant, which not only lowers the interfacial tension (and hence the cohesive strength) of the drop but also simultaneously renders the interface nonductile or brittle at high enough concentration. We have identified the relevant thermodynamic parameter, viz., the sum of interfacial tension, sigma, and the Gibbs elasticity, epsilon, which plays a decisive role in determining the mode of drop breakup. The parameter (epsilon + sigma) represents the internal restoration stress of a liquid drop opposing rapid, short-time-scale perturbations or local deformations in the drop shape under the influence of external impulses or stresses. A thermodynamic "state" diagram of (epsilon + sigma) versus interfacial area per surfactant molecule adsorbed at the drop interface shows a "maximum" at a critical transition concentration (ctc). Below this concentration of the surfactant, the drop undergoes tip streaming or pinch off. Above this concentration, the drop may undergo catastrophic disintegration if the external stress is high enough to overcome the ultimate cohesive strength of the drop's interface

Regional variations in MR relaxation of hip joint cartilage in subjects with and without femoralacetabular impingement

The objective of this study was to analyze regional variations of magnetic resonance (MR) relaxation times (T(1ρ) and T(2)) in hip joint cartilage of healthy volunteers and subjects with femoral acetabular impingement (FAI). Morphological and quantitative images of the hip joints of 12 healthy volunteers and 9 FAI patients were obtained using a 3 T MR scanner. Both femoral and acetabular cartilage layers in each joint were semi-automatically segmented on sagittal 3D high-resolution spoiled gradient echo (SPGR) images. These segmented regions of interest (ROIs) were automatically divided radially into twelve equal sub-regions (30(0) intervals) based on the fitted center of the femur head. The mean value of T(1ρ)/T(2) was calculated in each subregion after superimposing the divided cartilage contours on the MR relaxation (T(1ρ)/T(2)) maps to quantify the relaxation times. T(1ρ) and T(2) relaxation times of the femoral cartilage were significantly higher in FAI subjects compared to healthy controls (39.9 ± 3.3 msec in FAI vs. 35.4 ± 2.3 msec in controls for T(1ρ) (P = 0.0020); 33.9 ± 3.1 msec in FAI vs. 31.1 ± 1.7 msec in controls for T(2) (P = 0.0160)). Sub-regional analysis showed significantly different T(1ρ) and T(2) relaxation times in the anterior-superior region (R9) of the hip joint cartilage between subjects with FAI and healthy subjects, suggesting possible regional differences in cartilage matrix composition between these two groups. Receiver operating characteristic (ROC) analysis showed that subregional analysis in femoral cartilage was more sensitive in discriminating FAI joint cartilage from that of healthy joints than global analysis of the whole region (T(1ρ): area under the curve (AUC) = 0.981, P = 0.0001 for R9 sub-region; AUC = 0.901, P = 0.002 for whole region; T(2): AUC = 0.976, P = 0.0005 for R9 sub-region; AUC = 0.808, P = 0.0124 for whole region). The results of this study demonstrated regional variations in hip cartilage composition using MR relaxation times (T(1ρ) and T(2)) and suggested that analysis based on local regions was more sensitive than global measures in subjects with and without FAI