Cross-talk between α-synuclein post-translational modifications in yeast as model of Parkinson’s disease

Posttranslationale Modifikationen modulieren verschiedene Charakteristika von Proteinen. Sie können die Aktivität, Lokalisierung und Stabilität ihrer Substrate regulieren, verändern aber auch Eigenschaften und Strukturvon Proteinen, die mit Krankheiten assoziiert sind. Ein wichtiges Kennzeichen der Parkinson-Krankheit ist die Akkumulation von Proteinaggregaten (Lewy Körperchen). Dies führt zu neuronalem Zelltod durch verschiedene, bisher oft unbekannte Mechanismen. α-Synuclein, ein präsynaptisches, neuronales Protein, ist der Hauptbestandteil der Lewy-Körperchen und spielt eine wichtige Rolle in der Pathogenese der Parkinson-Krankheit. Es unterliegt verschiedenen posttranslationalen Modifikationen unter pathologischen Bedingungen. Die Zytotoxizität und Aggregation von α-Synuclein kann in Hefe imitiert werden. In dieser Studie werden zwei wichtigen posttranslationalen Modifikationen von α-Synuclein, Sumoylierung und Phosphorylierung von Serin 129 (S129), untersucht. Heterolog exprimertes Wildtyp-α-Synuclein und die A30P Mutante sind in Hefe an den gleichen Resten, Lysin 96 (K96) und Lysin 102 (K102), sumoyliert wie im Menschen. Eine Absenkung des zellulären Pools des Ubiquitin-ähnlichen Proteins SUMO führte zu einer starken Wachstumsreduktion von Zellen, welche α-Synuclein exprimieren. Dies korrelierte mit einer erhöhten Zahl an Zellen, die Einschlüsse bildeten. Dies legt nahe, dass Sumoylierung die Hefen vor α-Synuclein vermittelter Toxizität und Einschlussbildung schützt. Die Expression von sumoylierungsdefizienten α-Synuclein verursachte die gleiche Wachstumsrate, was die protektive Rolle der α-Synuclein Sumoylierung in cis bestätigt. Eine Überexpression der humanen Kinasen GRK5 und PLK2 erhöhten den Anteil an S129 phosphoryierten α-Synuclein. Interessanterweise wurde die α-Synuclein–vermittelte Zytotoxizität in Zusammenhang mit einer beeinträchtigten Sumoylierung durch eine höhere Kinase-abhängige S129 α-Synuclein Phosphorylierungsrate kompensiert. Phosphorylierung reduzierte die Einschlussbildung und verminderte die Wachstumshemmung. Um mehr Einblicke in eine plausible wechselseitige Beeinflussung zwischen α-Synuclein Sumoylierung und S129 Phosphorylierung zu erhalten, wurde die Beseitigung der α-Synuclein Aggregate beobachtet. Promotor „shut-off“ Studien wurden parallel mit chemischer Inhibition der zellulären Abbauwege durchgeführt. In der Abwesenheit von SUMO wurden α-Synuclein-Aggregate hauptsächlich durch das Ubiquitin-Proteasom-System abgebaut. Dies legt nahe, dass Sumoylierung den Abbau der α-Synuclein-Aggregate durch Autophagie unterstützt. In Anwesenheit der humanen Kinasen GRK5 oder PLK2, wurden die sumoylierungsdefizienten α-Synuclein-Aggregate Kinasen abhängig sowohl dem Ubiquitin-Proteasom als auch dem Autophagie-System zugeführt. Dies ging einher mit einem veränderten Ubiquitinierungs-Profil von α-Synuclein. GRK5 war in der Lage den Abbau von sumoylierungsdefizienten α-Synuclein-Aggregaten durch Autophagie partiell zu retten und außerdem das Proteasom-System zu unterstützen. In Abwesenheit von SUMO, wenn PLK2 überexprimiert wird, trugen beide Abbauwege gleich stark zur Beseitigung der α-Synuclein-Aggregate bei. Diese wechselseitige Beeinflussung zwischen α-Synuclein Phosphorylierung und Sumoylierung könnte neue Wege für eine therapeutische Intervention in der Parkinsonkrankheit und anderen Synucleinopathien eröffnen

Late Cenozoic to Present Kinematic of the North to Eastern Iran Orogen: Accommodating Opposite Sense of Fault Blocks Rotation

The opposite-sense fault block rotation across the continental strike-slip faulting plays an important role in accommodating crustal deformation in the north of the East Iran orogen. This research constrains the post-Neogene kinematics of the NW-SE to E-W left-lateral transpressional zones at the northern termination of the N-S striking right-lateral Neh fault system in the East Iran orogen. Using two case studies, we analyzed the NW-SE Birjand splay and the E-W Shekarab transpression zone by analysis of satellite images, structural features, fault geometry and kinematics, GPS (Global Positioning System) velocities, fault- and earthquake-slip stress inversion, and paleomagnetic data. Our results show two distinctive regions of opposite-sense fault block rotations and with different rotation rates. As an asymmetric arc, the Birjand splay displays a transition from the prevailing N-S right lateral shear in the east to NW-SE left lateral transpression in the middle and E-W left lateral shear in the west. In the east, with clockwise fault block rotation, the N-S right lateral faults and the NW-SE oblique left-lateral reverse faults constitute push-ups through the restraining fault bends. In the west, with counterclockwise fault block rotation, the Shekarab transpression zone is associated with the duplex, pop-up, and shear folds. Our suggested kinematic model reveals that the N-S right-lateral shear is consumed on the left-lateral transpressional zones through the vertical axis fault block rotation. This led to an E-W shortening and N-S along-strike lengthening in the East Iran orogen. This research improves our understanding of how opposite fault block rotations accommodate India- and Eurasia-Arabia convergence in the north of the East Iran orogen. The suggested model has implications in the kinematic evolution of intra-plate strike-slip faulting through continental collision tectonics

Paleoseismological and morphological evidence of slip rate variations along the North Tabriz fault (NW Iran)

International audienceNorthwest Iran is characterized by a high level of historical and instrumental seismicity related to the ongoing convergence between the Arabian and Eurasian plates. In this region, the main right-lateral strike-slip fault known as the North Tabriz fault (NTF) forms the central portion of a large crustal fault system called the Tabriz fault system (TFS). The NTF is a major seismic source along which at least three strong and destructive earthquakes have occurred since 858 AD. The two most recent destructive seismic events occurred in 1721 AD and 1780 AD, rupturing the SE and NW fault segments, respectively. This paper reports paleoseismological and quantitative geomorphologic investigations on the SE segment of the NTF, between the cities of Bostanabad and Tabriz. These observations help to improve our understanding of the seismic hazard for Tabriz city and its surrounding areas. Our field investigations revealed evidence of successive faulting events since the Late Quaternary. Paleoseismic investigations indicate that since 33.5 kyr, the SE segment of the NTF has experienced at least three major (M>7.5) seismic events, including the 1721 AD earthquake (M=7.6–7.7). Along the NW segment of the fault, however, our results suggest that the amount of strong (M~7.5) seismic events during the same period is significantly greater than along the SE segment. One possible explanation of such a difference in seismic activity is that the Late Quaternary-Holocene coseismic slip rate is decreasing along the NTF from the northwest to the southeast. This explanation contradicts the former hypothesis of a constant slip rate along the whole length of the NTF. In addition, more distributed deformation along several parallel fault branches, in a wider fault zone of the SE segment of the NTF may be considered as additional evidence for the estimation of lower rate of deformation along the fault segment. Such a slip distribution pattern can explain the existence of smaller (~300 m) Pliocene-Quaternary cumulative dextral offsets along the SE fault segment than the measured cumulative offsets along the NW segment (~800 m) of the NTF

Systematic comparison of the effects of Alpha-synuclein mutations on its oligomerization and aggregation

Copyright: © 2014 Lázaro et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Aggregation of alpha-synuclein (ASYN) in Lewy bodies and Lewy neurites is the typical pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Furthermore, mutations in the gene encoding for ASYN are associated with familial and sporadic forms of PD, suggesting this protein plays a central role in the disease. However, the precise contribution of ASYN to neuronal dysfunction and death is unclear. There is intense debate about the nature of the toxic species of ASYN and little is known about the molecular determinants of oligomerization and aggregation of ASYN in the cell. In order to clarify the effects of different mutations on the propensity of ASYN to oligomerize and aggregate, we assembled a panel of 19 ASYN variants and compared their behaviour. We found that familial mutants linked to PD (A30P, E46K, H50Q, G51D and A53T) exhibited identical propensities to oligomerize in living cells, but had distinct abilities to form inclusions. While the A30P mutant reduced the percentage of cells with inclusions, the E46K mutant had the opposite effect. Interestingly, artificial proline mutants designed to interfere with the helical structure of the N-terminal domain, showed increased propensity to form oligomeric species rather than inclusions. Moreover, lysine substitution mutants increased oligomerization and altered the pattern of aggregation. Altogether, our data shed light into the molecular effects of ASYN mutations in a cellular context, and established a common ground for the study of genetic and pharmacological modulators of the aggregation process, opening new perspectives for therapeutic intervention in PD and other synucleinopathies.This work was supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB).info:eu-repo/semantics/publishedVersio

Late Cenozoic to Present Kinematic of the North to Eastern Iran Orogen: Accommodating Opposite Sense of Fault Blocks Rotation

The opposite-sense fault block rotation across the continental strike-slip faulting plays an important role in accommodating crustal deformation in the north of the East Iran orogen. This research constrains the post-Neogene kinematics of the NW-SE to E-W left-lateral transpressional zones at the northern termination of the N-S striking right-lateral Neh fault system in the East Iran orogen. Using two case studies, we analyzed the NW-SE Birjand splay and the E-W Shekarab transpression zone by analysis of satellite images, structural features, fault geometry and kinematics, GPS (Global Positioning System) velocities, fault- and earthquake-slip stress inversion, and paleomagnetic data. Our results show two distinctive regions of opposite-sense fault block rotations and with different rotation rates. As an asymmetric arc, the Birjand splay displays a transition from the prevailing N-S right lateral shear in the east to NW-SE left lateral transpression in the middle and E-W left lateral shear in the west. In the east, with clockwise fault block rotation, the N-S right lateral faults and the NW-SE oblique left-lateral reverse faults constitute push-ups through the restraining fault bends. In the west, with counterclockwise fault block rotation, the Shekarab transpression zone is associated with the duplex, pop-up, and shear folds. Our suggested kinematic model reveals that the N-S right-lateral shear is consumed on the left-lateral transpressional zones through the vertical axis fault block rotation. This led to an E-W shortening and N-S along-strike lengthening in the East Iran orogen. This research improves our understanding of how opposite fault block rotations accommodate India- and Eurasia-Arabia convergence in the north of the East Iran orogen. The suggested model has implications in the kinematic evolution of intra-plate strike-slip faulting through continental collision tectonics

Late Cenozoic to Present Kinematic of the North to Eastern Iran Orogen: Accommodating Opposite Sense of Fault Blocks Rotation

The opposite-sense fault block rotation across the continental strike-slip faulting plays an important role in accommodating crustal deformation in the north of the East Iran orogen. This research constrains the post-Neogene kinematics of the NW-SE to E-W left-lateral transpressional zones at the northern termination of the N-S striking right-lateral Neh fault system in the East Iran orogen. Using two case studies, we analyzed the NW-SE Birjand splay and the E-W Shekarab transpression zone by analysis of satellite images, structural features, fault geometry and kinematics, GPS (Global Positioning System) velocities, fault- and earthquake-slip stress inversion, and paleomagnetic data. Our results show two distinctive regions of opposite-sense fault block rotations and with different rotation rates. As an asymmetric arc, the Birjand splay displays a transition from the prevailing N-S right lateral shear in the east to NW-SE left lateral transpression in the middle and E-W left lateral shear in the west. In the east, with clockwise fault block rotation, the N-S right lateral faults and the NW-SE oblique left-lateral reverse faults constitute push-ups through the restraining fault bends. In the west, with counterclockwise fault block rotation, the Shekarab transpression zone is associated with the duplex, pop-up, and shear folds. Our suggested kinematic model reveals that the N-S right-lateral shear is consumed on the left-lateral transpressional zones through the vertical axis fault block rotation. This led to an E-W shortening and N-S along-strike lengthening in the East Iran orogen. This research improves our understanding of how opposite fault block rotations accommodate India- and Eurasia-Arabia convergence in the north of the East Iran orogen. The suggested model has implications in the kinematic evolution of intra-plate strike-slip faulting through continental collision tectonics

Fault-kinematic and geomorphic observations along the North Tehran Thrust and Mosha Fasham Fault, Alborz mountains Iran: Implications for fault-system evolution and interaction in a changing tectonic regime

Neighbouring faults can interact, potentially link up and grow, and consequently increase the seismic and related natural hazards in their vicinity. Despite evidence of Quaternary faulting, the kinematic relationships between the neighbouring Mosha Fasham Fault (MFF) and the North Tehran Thrust (NTT) and their temporal evolution in the Alborz mountains are not well understood. The ENE-striking NTT is a frontal thrust that delimits the Alborz mountains to the south with a 2000 m topographic front with respect to the proximal Tehran plain. However, no large instrumentally recorded earthquakes have been attributed to that fault. In contrast, the sigmoidally shaped MFF is a major strike-slip fault, located within the Alborz Mountains. Sinistral motion along the eastern part of the MFF is corroborated by microseismicity and fault kinematic analysis, which documents recent transtensional deformation associated with NNE-SSW oriented shortening. To better understand the activity of these faults on different timescales, we combined fault-kinematic analysis and geomorphic observations, to infer the kinematic history of these structures. Our fault kinematic study reveals an early dextral shear for the NTT and the central MFF, responsible for dextral strike-slip and oblique reverse faulting during NW-oriented shortening. This deformation regime was superseded by NE-oriented shortening, associated with sinistral-oblique thrusting along the NTT and the central-western MFF, sinistral strike-slip motion along subsidiary faults in the central MFF segment, and folding and tilting of Eocene to Miocene units in the MFF footwall. Continued thrusting along the NTT took place during the Quaternary. However, folding in the hanging wall and sinistral stream-offsets indicate a left-oblique component and Quaternary strike-slip reactivation of the eastern NTT-segment, close to its termination. This complex history of faulting under different stress directions has resulted in a composite landscape with inherited topographic signatures. Our study shows that the topography of the hanging wall of the NTT reflects a segmentation into sectors with semi-independent uplift histories. Areas of high topographic residuals and apparent high uplift underscore the fault kinematics. Combined, our data suggest an early mechanical linkage of the NTT and MFF fault systems during a former dextral transpressional stage, caused by NW-compression. During NE-oriented shortening, the NTT and MFF were reactivated and incorporated into a nascent transpressional duplex. The youngest manifestation of motion in this system is sinistral transtension. However, this deformation is not observed everywhere and has not yet resulted in topographic inversion. © 2009 The Authors Journal compilation © 2009 RAS

Active-couple indentation in geodynamics of NNW Iran: Evidence from synchronous left- and right-lateral co-linear seismogenic faults in western Alborz and Iranian Azerbaijan domains

International audienceSituated within the central portion of the Arabia-Eurasia collision zone, NNW Iran exhibits an interesting active tectonic context characterized by synchronous left- and right-lateral co-linear seismogenic faults along the adjacent WNW-striking West-Central Alborz (e.g. the Rudbar earthquake fault) and Iranian Azerbaijan (e.g. the North Tabriz seismogenic fault). These structural domains are deforming as a single deformable geomechanical territory between the nearly rigid Central Iran and South Caspian domains to the SSW and NNE, respectively. In this paper, we analyze tectonic interactions of these active structural domains and their influence on the geodynamics of NNW Iran based on morphotectonic and seismological investigations. Indentation tectonics is suggested to play an important role in the geodynamics of this territory. At a plate tectonic scale, the rigid Arabian plate acts as the main indenter which bulldozes the less rigid crustal domains ahead into folded belts (within Zagros and Caucasus to the north) and pushes other blocks aside. In this deformation system, the South Caspian domain acts as a backstop against southern and western deformation zones. The structural domains of Alborz (to the east) and Iranian Azerbaijan Caucasus (to the west) are separated by the NNW-striking Astara-Talesh dextral transpressional zone. Analysis of morphotectonic features and focal mechanisms conducted in this central portion of NNW Iran confirms dextral faulting localized along the NNW-striking deformation zone, which is in agreement with the observed reverse earthquake faulting on west-dipping planes. We also discuss the contraction trajectories derived from kinematics and geometry of active folding and faulting features observed within NNW Iran. Our study highlights two prominent sets of fan-shaped trajectories dominating in the west and east sides of the N–S zone in the Astara-Zanjan direction. We propose a couple-indentation geodynamic model to explain the fan-shaped pattern of these two laterally convergent sets of trajectories within the Talesh-Azerbaijan and Alborz domains