9 research outputs found
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Inhibition of LRRK2 kinase activity stimulates macroautophagy
Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most important genetic contributors to Parkinson's disease. LRRK2 has been implicated in a number of cellular processes, including macroautophagy. To test whether LRRK2 has a role in regulating autophagy, a specific inhibitor of the kinase activity of LRRK2 was applied to human neuroglioma cells and downstream readouts of autophagy examined. The resulting data demonstrate that inhibition of LRRK2 kinase activity stimulates macroautophagy in the absence of any alteration in the translational targets of mTORC1, suggesting that LRRK2 regulates autophagic vesicle formation independent of canonical mTORC1 signaling. This study represents the first pharmacological dissection of the role LRRK2 plays in the autophagy/lysosomal pathway, emphasizing the importance of this pathway as a marker for LRRK2 physiological function. Moreover it highlights the need to dissect autophagy and lysosomal activities in the context of LRRK2 related pathologies with the final aim of understanding their aetiology and identifying specific target for disease modifying therapies in patients
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mTOR independent alteration in ULK1 Ser758 phosphorylation following chronic LRRK2 kinase inhibition
Unc-51 Like Kinase 1 (ULK1) is a critical regulator of the biogenesis of autophagosomes, the central component of the catabolic macroautophagy pathway. Regulation of ULK1 activity is dependent upon several phosphorylation events acting to repress or activate the enzymatic function of this protein. Phosphorylation of Ser758 ULK1 has been linked to repression of autophagosome biogenesis and was thought to be exclusively dependent upon mTOR complex 1 kinase activity. In this study, a novel regulation of Ser758 ULK1 phosphorylation is reported following prolonged inhibition of the Parkinson's disease linked protein Leucine Rich Repeat Kinase 2 (LRRK2). Here, modulation of Ser758 ULK1 phosphorylation following LRRK2 inhibition is decoupled from the repression of autophagosome biogenesis and independent of mTOR complex 1 activity
Middle Neolithic pits and a burial at West Amesbury, Wiltshire
Excavations on the south-eastern slopes of King Barrow Ridge, 1.5 km east of Stonehenge, revealed five pits, a grave and other features of Middle Neolithic date. Analysis of the pit assemblages and the partial inhumation interred in the grave has provided insights into lifeways in this landscape in the late fourth millennium cal BC. Evidence suggests that the area was visited by a pastoralist, mobile community on a semi-regular basis for a significant period, in late autumn or winter. Selected remnants of craft-working and consumption were deposited in pits, before deliberate infilling. These depositions repeatedly memorialised activity on the hillside at a time of contemporary activity elsewhere on King Barrow Ridge and at the future site of Stonehenge. Middle Neolithic pits are present in significant numbers across King Barrow Ridge, and alongside pits in the Durrington area, form one of the densest concentrations of such activity in the region. Long distance mobility is suggested by the possible Irish origins of the inhumation, the first Middle Neolithic individual excavated in the environs of Stonehenge. Whilst of significance for understanding the Middle Neolithic in the WHS and the region, this research also hints at the roots of Late Neolithic monumentalisation of this landscape
Recent investigations at two long barrows and reflections on their context in the Stonehenge World Heritage Site and environs
Recent Investigations at Two Long Barrows and Reflections on their Context in the Stonehenge World Heritage Site and Environs
Recent geophysical surveys and excavations at Druid's Lodge Estate, in fields west of the Diamond Wood in the Stonehenge World Heritage Site (SWHS), have confirmed the existence of the Winterbourne Stoke 71 long barrow and discovered a new long barrow (Winterbourne Stoke 86) a short distance to the south. Survey and excavation show internal features at both barrows and, alongside aerial photography, suggest that both monuments were destroyed during later prehistory. These barrows are part of a cluster around the head of the Wilsford dry valley. We review long barrows in the SWHS and environs to contextualise these discoveries, demonstrating a diversity of internal features, barrow sizes and morphologies. Chronological modelling is used to place the SWHS barrows in their inter-regional timescape and to understand the timings of the first appearance of monument types of the 4th millennium cal BC. Local topography appears to be the key factor in determining the alignment of long barrows, but the eastern ends of barrows appear to be significant. Long barrows are also considered in relation to causewayed enclosures, and movement around the landscape. Long barrows are an important structuring monument in the later Neolithic and Bronze Age landscape, but their importance is mediated by their location relative to Stonehenge, and access to the monument from the south. There is a clear pattern of differential preservation of long barrows away from the vicinity of Stonehenge. Further field research is necessary to achieve a better understanding of long barrows in the SWHS, and it is hoped that this article stimulates interest in these highly significant monuments. This article also provides an interactive map of the SWHS, linking to simplified plans of long barrows in the study area, additional information and references for further reading for each barrow. Appendices are provided containing specialist methodologies and/or data from the geophysical surveys and the Historic England excavation, and primary excavation data from the Historic England excavation is downloadable via the Archaeology Data Service (Historic England 2018)