Alpha-synuclein suppresses mitochondrial protease ClpP to trigger mitochondrial oxidative damage and neurotoxicity.

Both α-Synuclein (αSyn) accumulation and mitochondrial dysfunction have been implicated in the pathology of Parkinson's disease (PD). Although studies suggest that αSyn and its missense mutant, A53T, preferentially accumulate in the mitochondria, the mechanisms by which αSyn and mitochondrial proteins regulate each other to trigger mitochondrial and neuronal toxicity are poorly understood. ATP-dependent Clp protease (ClpP), a mitochondrial matrix protease, plays an important role in regulating mitochondrial protein turnover and bioenergetics activity. Here, we show that the protein level of ClpP is selectively decreased in αSyn-expressing cell culture and neurons derived from iPS cells of PD patient carrying αSyn A53T mutant, and in dopaminergic (DA) neurons of αSyn A53T mice and PD patient postmortem brains. Deficiency in ClpP induces an overload of mitochondrial misfolded/unfolded proteins, suppresses mitochondrial respiratory activity, increases mitochondrial oxidative damage and causes cell death. Overexpression of ClpP reduces αSyn-induced mitochondrial oxidative stress through enhancing the level of Superoxide Dismutase-2 (SOD2), and suppresses the accumulation of αSyn S129 phosphorylation and promotes neuronal morphology in neurons derived from PD patient iPS cells carrying αSyn A53T mutant. Moreover, we find that αSyn WT and A53T mutant interact with ClpP and suppress its peptidase activity. The binding of αSyn to ClpP further promotes a distribution of ClpP from soluble to insoluble cellular fraction in vitro and in vivo, leading to reduced solubility of ClpP. Compensating for the loss of ClpP in the substantia nigra of αSyn A53T mice by viral expression of ClpP suppresses mitochondrial oxidative damage, and reduces αSyn pathology and behavioral deficits of mice. Our findings provide novel insights into the mechanism underlying αSyn-induced neuronal pathology, and they suggest that ClpP might be a useful therapeutic target for PD and other synucleinopathies.

Preclinical evaluation of the selective small-molecule UBA1 inhibitor, TAK-243, in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy for which new therapeutic approaches are required. One such potential therapeutic strategy is to target the ubiquitin-like modifier-activating enzyme 1 (UBA1), the initiating enzyme in the ubiquitylation cascade in which proteins are tagged with ubiquitin moieties to regulate their degradation or function. Here, we evaluated TAK-243, a first-in-class UBA1 inhibitor, in preclinical models of AML. In AML cell lines and primary AML samples, TAK-243 induced cell death and inhibited clonogenic growth. In contrast, normal hematopoietic progenitor cells were more resistant. TAK-243 preferentially bound to UBA1 over the related E1 enzymes UBA2, UBA3, and UBA6 in intact AML cells. Inhibition of UBA1 with TAK-243 decreased levels of ubiquitylated proteins, increased markers of proteotoxic stress and DNA damage stress. In vivo, TAK-243 reduced leukemic burden and targeted leukemic stem cells without evidence of toxicity. Finally, we selected populations of AML cells resistant to TAK-243 and identified missense mutations in the adenylation domain of UBA1. Thus, our data demonstrate that TAK-243 targets AML cells and stem cells and support a clinical trial of TAK-243 in this patient population. Moreover, we provide insight into potential mechanisms of acquired resistance to UBA1 inhibitors.

Massive Ischemic Stroke Due to Pulmonary Barotrauma and Cerebral Artery Air Embolism During Commercial Air Travel.

BACKGROUND Air embolism into the systemic arterial circulation secondary to pulmonary barotrauma has rarely been reported. Herein, we report the clinical course of an extremely rare presentation of cerebral air embolism likely due to ruptured pulmonary bullae during commercial air travel. CASE REPORT A 65-year-old man suddenly became unconscious during an airplane descent. Upon landing, he was immediately transferred to the nearest emergency department where he was intubated for airway protection. His head CT angiogram showed multiple air pockets in the right parietal lobe suspicious for multiple air emboli. His chest CT scan showed multiple large bullae in the left upper and lower lobes as well as diffusely emphysematous lung tissue. After initial stabilization, he underwent emergent hyperbaric oxygen treatment (HBOT) in the multiplace chamber at 2.8 atmospheres. The patient tolerated HBOT well with no complications. However, his neurologic status deteriorated in the following 24 hours due to progression of his cerebral edema and mass effects. The patient's clinical status was discussed with his family and the decision was made to withdraw life-sustaining measures. He died shortly after withdrawal of life support. Post-mortem examination confirmed the presence of very large bullae in the lungs bilaterally. CONCLUSIONS Spontaneous cerebral air embolism is a possible complication of ruptured pulmonary bullae during air travel. HBOT is well-tolerated and may be used with caution even in the presence of emphysematous bullae.

Conversion of the Seattle Angina Questionnaire into EQ-5D utilities for ischemic heart disease: a systematic review and catalog of the literature.

BACKGROUND: There is a paucity of preference-based (utility) measures of health-related quality of life for patients with ischemic heart disease (IHD); in contrast, the Seattle Angina Questionnaire (SAQ) is a widely used descriptive measure. Our objective was to perform a systematic review of the literature to identify IHD studies reporting SAQ scores in order to apply a mapping algorithm to convert these to preference-based scores for secondary use in economic evaluations. METHODS: Relevant articles were identified in MEDLINE (Ovid), EMBASE (Ovid), Cochrane Library (Wiley), HealthStar (Ovid), and PubMed from inception to 2012. We previously developed and validated a mapping algorithm that converts SAQ descriptive scores to European Quality of Life-5 Dimensions (EQ-5D) utility scores. In the current study, this mapping algorithm was used to estimate EQ-5D utility scores from SAQ scores. RESULTS: Thirty-six studies met the inclusion criteria. The studies were categorized into three groups, ie, general IHD (n=13), acute coronary syndromes (n=4), and revascularization (n=19). EQ-5D scores for patients with general IHD were in the range of 0.605-0.843 at baseline, and increased to 0.649-0.877 post follow-up. EQ-5D scores for studies of patients with recent acute coronary syndromes increased from 0.706-0.796 at baseline to 0.795-0.942 post follow-up. The revascularization studies had EQ-5D scores in the range of 0.616-0.790 at baseline, and increased to 0.653-0.928 after treatment; studies that focused only on coronary artery bypass grafting increased from 0.643-0.788 at baseline to 0.653-0.928 after grafting, and studies that focused only on percutaneous coronary intervention increased in score from 0.616-0.790 at baseline to 0.668-0.897 after treatment. CONCLUSION: In this review, we provide a catalog of estimated health utility scores across a wide range of disease severity and following various interventions in patients with IHD. Our catalog of EQ-5D scores can be used in IHD-related economic evaluations.