Stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation and toxicity of α-synuclein in vivo

The predominantly pre-synaptic intrinsically disordered protein α-synuclein is prone to misfolding and aggregation in synucleinopathies, such as Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). Molecular chaperones play important roles in protein misfolding diseases and members of the chaperone machinery are often deposited in Lewy bodies. Here, we show that the Hsp90 co-chaperone STI1 co-immunoprecipitated α-synuclein, and co-deposited with Hsp90 and Hsp70 in insoluble protein fractions in two mouse models of α-synuclein misfolding. STI1 and Hsp90 also co-localized extensively with filamentous S129 phosphorylated α-synuclein in ubiquitin-positive inclusions. In PD human brains, STI1 transcripts were increased, and in neurologically healthy brains, STI1 and α-synuclein transcripts correlated. Nuclear Magnetic Resonance (NMR) analyses revealed direct interaction of α-synuclein with STI1 and indicated that the STI1 TPR2A, but not TPR1 or TPR2B domains, interacted with the C-terminal domain of α-synuclein. In vitro, the STI1 TPR2A domain facilitated S129 phosphorylation by Polo-like kinase 3. Moreover, mice over-expressing STI1 and Hsp90ß presented elevated α-synuclein S129 phosphorylation accompanied by inclusions when injected with α-synuclein pre-formed fibrils. In contrast, reduced STI1 function decreased protein inclusion formation, S129 α-synuclein phosphorylation, while mitigating motor and cognitive deficits as well as mesoscopic brain atrophy in α-synuclein-over-expressing mice. Our findings reveal a vicious cycle in which STI1 facilitates the generation and accumulation of toxic α-synuclein conformers, while α-synuclein-induced proteostatic stress increased insoluble STI1 and Hsp90

A cohort study reporting normal oximetry values in healthy infants under 4 months of age using Masimo technology

Objective: To determine sleeping saturation indices in healthy infants using a modern pulse oximeter with motion artefact extraction technology. Design: Prospective cohort. Setting: Home. Subjects: Healthy term infants. Intervention: Nocturnal pulse oximetry at home at 1 month of age (Recording 1) and repeated at age 3-4 months (Recording 2). Parents documented sleep times. Visi-Download software (Stowood Scientific) analysed data with artefact and wake periods removed. Main outcome measures: Saturations (SAT50), desaturation index &gt;4% (DI4) and &gt;3% (DI3) from baseline/hour, delta index 12 s (DI12s), minimum saturations (SATmin), percentage time with saturations below 90% and 92%. Results: Forty-five babies were studied at 1 month and 38 babies at 3-4 months. Mean (CI) SAT50, DI4, DI3, DI12s and SATmin (CI) were 97.05 (96.59 to 97.52), 16.16 (13.72 to 18.59), 25.41 (22.00 to 28.82), 0.96 (0.88 to 1.04) and 80.4% (78.8% to 82.0%) at 1 month, respectively, and 97.65 (97.19 to 98.12), 8.12 (6.46 to 9.77), 13.92 (11.38 to 16.47), 0.72 (0.65 to 0.78) and 84.7% (83.3% to 86.1%) at 3-4 months. Median (CI) percentage times with saturations below 90% and 92% were 0.39 (0.26 to 0.55) and 0.82 (0.60 to 1.23), respectively, at 1 month and 0.11 (0.06 to 0.20) and 0.25 (0.17 to 0.44) at 3-4 months. For paired samples (n=32) DI4 (P=0.006), DI3 (P=0.03), DI12s (P=0.001), percentage time with saturations below 90% (P=0.001) and 92% (P=0.000) all fell significantly and SATmin (P=0.004) rose between the two recordings. Conclusion: Desaturation indices are substantially higher in young infants than older children where a DI4 over 4 is considered abnormal. These decrease by 3-4 months of age but still remain elevated compared with older children.</p

Oxidative Stress-Induced Misfolding and Inclusion Formation of Nrf2 and Keap1

Cells that experience high levels of oxidative stress respond by inducing antioxidant proteins through activation of the protein transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 is negatively regulated by the E3 ubiquitin ligase Kelch-like ECH-associated protein 1 (Keap1), which binds to Nrf2 to facilitate its ubiquitination and ensuing proteasomal degradation under basal conditions. Here, we studied protein folding and misfolding in Nrf2 and Keap1 in yeast, mammalian cells, and purified proteins under oxidative stress conditions. Both Nrf2 and Keap1 are susceptible to protein misfolding and inclusion formation upon oxidative stress. We propose that the intrinsically disordered regions within Nrf2 and the high cysteine content of Keap1 contribute to their oxidation and the ensuing misfolding. Our work reveals previously unexplored aspects of Nrf2 and Keap1 regulation and/or dysregulation by oxidation-induced protein misfolding

Age and frailty are independently associated with increased COVID-19 mortality and increased care needs in survivors: results of an international multi-centre study

Introduction: Increased mortality has been demonstrated in older adults with coronavirus disease 2019 (COVID-19), but the effect of frailty has been unclear. Methods: This multi-centre cohort study involved patients aged 18 years and older hospitalised with COVID-19, using routinely collected data. We used Cox regression analysis to assess the impact of age, frailty and delirium on the risk of inpatient mortality, adjusting for sex, illness severity, inflammation and co-morbidities. We used ordinal logistic regression analysis to assess the impact of age, Clinical Frailty Scale (CFS) and delirium on risk of increased care requirements on discharge, adjusting for the same variables. Results: Data from 5,711 patients from 55 hospitals in 12 countries were included (median age 74, interquartile range [IQR] 54–83; 55.2% male). The risk of death increased independently with increasing age (>80 versus 18–49: hazard ratio [HR] 3.57, confidence interval [CI] 2.54–5.02), frailty (CFS 8 versus 1–3: HR 3.03, CI 2.29–4.00) inflammation, renal disease, cardiovascular disease and cancer, but not delirium. Age, frailty (CFS 7 versus 1–3: odds ratio 7.00, CI 5.27–9.32), delirium, dementia and mental health diagnoses were all associated with increased risk of higher care needs on discharge. The likelihood of adverse outcomes increased across all grades of CFS from 4 to 9. Conclusion: Age and frailty are independently associated with adverse outcomes in COVID-19. Risk of increased care needs was also increased in survivors of COVID-19 with frailty or older age.</p

Students' participation in collaborative research should be recognised

Letter to the editor