Alpha synuclein can be phosphorylated at serine129 (P‐S129), and the presence of highly phosphorylated α‐synuclein in Lewy bodies suggests changes to its phosphorylation status has an important pathological role. We demonstrate that the kinase(s) responsible for α‐synuclein S129 phosphorylation is constitutively active in SH‐SY5Y cells and involves casein kinase 2 activity. Increased oxidative stress or proteasomal inhibition caused significant elevation of P‐S129 α‐synuclein levels. Under these conditions, similar increases in P‐S129 α‐synuclein were found in both sodium dodecyl sulphate lysates and Triton extracts indicating the phosphorylated protein was soluble and did not lead to aggregation. The rate of S129 phosphorylation was increased in response to proteasomal inhibition indicating a higher activity of the relevant kinase. Cells expressing the phosphorylation mimic, S129D α‐synuclein increased cell death and enhanced sensitivity to epoxomycin exposure. Proteasomal inhibition markedly decreased S129D α‐synuclein turnover suggesting proteasomal inhibition leads to the accumulation of P‐S129 α‐synuclein through an increase in the kinase activity and a decrease in protein turnover resulting in increased cell death. We conclude that S129 phosphorylation is toxic to dopaminergic cells and both the levels of S129 phosphorylated protein and its toxicity are increased with proteasomal inhibition emphasising the interdependence of these pathways in Parkinson’s disease pathogenesis.

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Compared with young patients, propofol-assisted DBE in the elderly is safe and has a high diagnostic yield.

Background and study aims Oropharyngeal intubation during Esophagogastroduodenoscopy (EGD) is uncomfortable, associated with aerosol generation and transmission of airborne microbes. Less-invasive alternatives may be better tolerated. In this study, patient tolerance and acceptability of EGD and transnasal endoscopy (TNE) have been compared with magnet-controlled capsule endoscopy (MACE). Patients and methods A comparison of MACE with EGD and TNE in the investigation of dyspepsia was performed. Factors affecting patient tolerance and acceptability were examined using the Endoscopy Concerns Scale (ECS) and Universal Patient Centeredness Questionnaire (UPC-Q). Results Patients were significantly more distressed (scoring least to most distress: 1–10) by gagging (6 vs 1), choking (5 vs 1), bloating (2 vs 1), instrumentation (4 vs 1), discomfort during (5 vs 1) and after (2 vs 1) EGD compared to MACE (all P < 0.0001). Patients were more distressed by instrumentation (5 vs 1) and discomfort during (5 vs 1) TNE compared to MACE (P = 0.001). Patients were more accepting of MACE than EGD and TNE with a UPC-Q score (scoring least to most acceptable: 0–100) lower for EGD (50 vs 98, P < 0.0001) and TNE (75 vs 88, P = 0.007) than MACE, and a post-procedure ECS score (scoring most to least acceptable: 10–100) higher for EGD (34 vs 11, P < 0.0001) and TNE (25 vs 10.5, P = 0.001) than MACE. MACE would be preferred by 83 % and 64 % of patients even if EGD or TNE respectively was subsequently recommended to obtain biopsies in half of examinations. Conclusions Gagging and choking during instrumentation, the main causes of patient distress during EGD, occurred less during TNE but tolerance, acceptability and patient experience favored MACE.