Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism

Mutations in GBA1, the gene encoding the lysosomal enzyme β-glucocerebrosidase (GCase), which cause Gaucher's disease, are the most frequent genetic risk factor for Parkinson's disease (PD). Here, we employ global proteomic and single-cell genomic approaches in stable cell lines as well as induced pluripotent stem cell (iPSC)-derived neurons and midbrain organoids to dissect the mechanisms underlying GCase-related neurodegeneration. We demonstrate that GCase can be imported from the cytosol into the mitochondria via recognition of internal mitochondrial targeting sequence-like signals. In mitochondria, GCase promotes the maintenance of mitochondrial complex I (CI) integrity and function. Furthermore, GCase interacts with the mitochondrial quality control proteins HSP60 and LONP1. Disease-associated mutations impair CI stability and function and enhance the interaction with the mitochondrial quality control machinery. These findings reveal a mitochondrial role of GCase and suggest that defective CI activity and energy metabolism may drive the pathogenesis of GCase-linked neurodegeneration

Wilhelm Neumann (1898-1965) - His life and his work with special regard to his role in the research of chemical warfare agents

Gegenstand der vorliegenden Untersuchung ist das Leben und Werk des deutschen Pharmakologen und Toxikologen Wilhelm Neumann (11. Februar 1898 - 15. April 1965). Wesentliche Erkenntnisse hierzu konnten aus Aktenbeständen des Bundesarchivs der Bundesrepublik Deutschland in Berlin-Lichterfelde, Freiburg im Breisgau, und Koblenz, des Dekanatsarchiv der Medizinischen Fakultät der Bayerischen Julius-Maximilians-Universität Würzburg, des Archivs der „Deutschen Gesellschaft für experimentelle und klinische Pharmakologie und Toxikologie“ in Mainz, des Scheringianums, dem Archiv der Schering AG in Berlin, des Staatsarchivs Würzburg und des Universitätsarchivs der Bayerischen Julius-Maximilians-Universität Würzburg gewonnen werden. Von 1919 bis 1923 studierte Wilhelm Neumann in Berlin Chemie und promovierte in der chemischen Abteilung des Preußischen Instituts für Infektionskrankheiten „Robert Koch“ zum Dr. phil. Im Jahr 1924 trat er eine Stelle als Privatassistent am Pharmakologischen Institut der Universität Würzburg unter der Leitung Ferdinand Flurys an. Parallel zu seiner Arbeit am Pharmakologischen Institut studierte er von 1929 bis 1934 an der Universität Würzburg Humanmedizin und promovierte zum Dr. med. 1937 folgte seine Habilitation und die Ernennung zum Dozenten. Weitere Stationen seiner wissenschaftlichen Laufbahn am Pharmakologischen Institut waren die Ernennungen zum planmäßigen Assistenten 1939, zum Konservator 1941 und zum außerplanmäßigen Professor 1942. Im Jahr 1937 nahm Wilhelm Neumann als Arzt der Reserve seine militärische Karriere im Sanitätsdienst der Wehrmacht auf. Während des Zweiten Weltkrieges war er als „beratender Arzt“ und als Wissenschaftler für die Wehrmacht tätig. Neumanns politischer Werdegang begann im Juli 1933 mit seinem Beitritt zur Veteranenorganisation Stahlhelm. Im Februar 1934 wurde er Mitglied der SA, und ab dem 1. Mai 1937 gehörte er der NSDAP an. Nach Ende des Zweiten Weltkrieges wurde Neumann im Zuge des Entnazifizierungsprozesses 1946 aus dem Staatsdienst entlassen. Das 1947 ergangene Spruchkammerurteil reihte ihn in die Gruppe der „Mitläufer“ ein. Infolgedessen konnte er 1948 wieder von der Universität Würzburg eingestellt werden. Im Jahr 1949 wurde er dort zum ordentlichen Professor für Pharmakologie und Toxikologie berufen. Von 1954 bis 1955 übte er das Amt des Dekans der Medizinischen Fakultät der Universität Würzburg aus. Am Pharmakologischen Institut der Universität Würzburg untersuchte Neumann zunächst die Chemie und Pharmakologie der herzwirksamen Glykoside. Ihm gelang auf diesem Gebiet die Reindarstellung eines neuen Wirkstoffs, der 1935 von der Firma Schering im Herzinsuffizienztherapeutikum Folinerin auf den Markt gebracht wurde. Auf toxikologischem Gebiet arbeitete er von 1925 bis 1945 mit Ferdinand Flury an gewerbetoxikologischen Projekten und in der chemischen Kampfstoff-Forschung. Als ordentlicher Professor widmete sich Wilhelm Neumann dann neben eigenen toxikologischen Arbeiten der Förderung der Toxikologie als Fachrichtung. Zu Beginn der 1950er Jahre befasste er sich mit tierischen Giften und erforschte die Toxikologie der Reizgase und der Luftverschmutzung. Von 1955 bis 1965 war Wilhelm Neumann Vorsitzender der DFG-Kommission zur Prüfung gesundheitsschädlicher Arbeitsstoffe.The present investigation deals with the life and work of the German pharmacologist and toxicologist Wilhelm Neumann (11th February 1898 to 15th April 1965). Relevant findings to this subject were gathered from files of the ”Bundesarchiv” of the Federal Republic of Germany in Berlin-Lichterfelde, Freiburg im Breisgau and Koblenz, of the Dean’s Archives of the Faculty of Medicine of the Bavarian Julius-Maximilians-University in Würzburg, of the Archives of the “Deutsche Gesellschaft für experimentelle und klinische Pharmakologie und Toxikologie” in Mainz, of the Scheringianum, the archives of Schering AG in Berlin, of the “Staatsarchiv Würzburg” and of the University Archives of the Julius- Maximilians- University Würzburg. Wilhelm Neumann studied chemistry in Berlin from 1919 to 1923 and did a doctor’s degree in the chemical department of the “Preußisches Institut für Infektionskrankheiten >”. In 1924 he accepted a post as a private assistant at the Pharmacological Institute of Würzburg University led by Ferdinand Flury. Parallel to his work at the Pharmacological Institute Neumann studied human medicine at Würzburg University from 1929 to 1934, ending with a doctor’s degree. In 1937 he qualified as a university lecturer and then as an assistant professor. Further stages of his scientific career at the Pharmacological Institute were the appointment to regular assistant in 1939, to curator in 1941 and to associate professor in 1942. In 1937 Wilhelm Neumann had started upon his military career as a reserve doctor in the medical corps of the “Wehrmacht”. During World War II he worked as a consultant doctor and as a scientist for the “Wehrmacht”. His political career had started in July 1933 with his joining the veterans’ organization “Stahlhelm”. In February 1934 he became a member of the “SA” and from 1st May 1937 he belonged to the “NSDAP”. After World War II Neumann was dismissed as a civil servant in the course of de-Nazification. In 1947 the court ruled that he was to be ranked with “Mitläufer”. Consequently he could be re-employed by the University of Würzburg. Here he was appointed full professsor for pharmacology and toxicology in 1949. From 1954 to 1955 he held the office of the Dean of the Faculty of Medicine at Würzburg University. At the Institute of Pharmacology of Würzburg University Neumann first investigated into the chemistry and pharmacology of glycosids. In this field he succeeded in the pure preparation of a new active substance, which in 1935 was put on the market by Schering Firm as the cardiac insufficiency therapeutics “Folinerin”. It is in the field of toxicology that he had co-operated with Ferdinand Flury from 1925 to 1945, dealing with projects of occupational toxicology and with chemical research of chemical warfare agents. As a professor Wilhelm Neumann then applied himself to the promotion of toxicology as a subject area, besides his own toxicological works. At the beginning of the 1950es he dealt with animal poisons and researched into the toxicology of irritant gases and of air pollution. From 1955 to 1965 Wilhelm Neumann was the chairman of the “DFG-Kommission zur Prüfung gesundheitsschädlicher Arbeitsstoffe“

Mental Health and Social Support Are Key Predictors of Resilience in German Women with Endometriosis during the COVID-19 Pandemic

Background: Endometriosis is a multifaceted chronic pain disorder that can have an impact on both physical and mental health. Women suffering from chronic pain may be more susceptible to various health disorders, especially during adversity, such as the COVID-19 pandemic. Previous research has identified resilience as a mediator between internal or external stressors and well-being. Methods: An online survey was conducted during the first wave of the COVID-19 pandemic in Germany through patient support groups of women with endometriosis. The Brief Resilience Score (BRS) was employed to evaluate resilience, while the PHQ-4 questionnaire was used to assess self-reported mental health. Univariate and multivariate logistic regression analyses were applied to determine resilience’s independent risk and protective parameters. Results: High educational level was found to be an independent supportive moderator of high resilience in women with a resilience score greater than the study population’s median (BRS > 2.66; OR 2.715; 95% CI 1.472–5.007; p = 0.001) but not in women in the highest resilience score quartile (BRS > 3.33). A decrease in perceived social support was detected to be the most powerful independent risk factor for low resilience: OR 0.541, 95% CI 0.307–0.952, p = 0.033 for predicting BRS > 2.66, and OR 0.397, 95% CI 0.189–0.832, p = 0.014 for predicting scores > 3.33 on the BRS scale. A high burden of mental health symptoms, as measured by the PHQ-4 scale, was negatively associated with resilience. Conclusions: Satisfying social support and good mental health were shown to be key resources for resilience. The results of this study may assist in the identification of women at risk for low resilience and the development of resilience-building strategies in patients with endometriosis

Predictors of Psychological Distress in Women with Endometriosis during the COVID-19 Pandemic

Background: Endometriosis is a multifaceted chronic pain condition that can have a negative impact on mental health. Patients suffering from chronic pain may face an additional psychological burden during adversity, such as the COVID-19 pandemic. The main aim of this research was to evaluate the prevalence of self-reported depression and anxiety, the influence of demographic, endometriosis-specific, pandemic-specific factors, and resilience on mental health outcomes of patients with endometriosis. Methods: An online survey was conducted through patient support groups of women suffering from endometriosis during the first wave of the COVID-19 pandemic. The PHQ-4 questionnaire, which combines two items of the Patient Health Questionnaire for Depression (PHQ-2) and two items from the Generalized Anxiety Disorder Scale (GAD-2) was used to assess self-reported mental health. The Brief Resilience Score (BRS) was employed to evaluate resilience. Independent risk and protective factors for mental health were investigated by multivariate logistic regression analyses. Results: The PHQ-4 questionnaire was completed by 274 respondents. More than 40% reached depression (PHQ-2) and anxiety (GAD-2) scores of ≥3, and more than 20% achieved PHQ-2 and GAD-2 scores of ≥5. High resilience was found to be a reliable and strong independent protector for the probability of developing adverse psychological outcomes: OR 0.295, p < 0.001 for developing generalized anxiety disorder (GAD-2 ≥ 3), and OR 0.467, p < 0.001 for having major depression (PHQ-2 ≥ 3). Conclusions: Pain-induced disability is an independent risk factor for developing major depression and anxiety, while resilience was identified as a potential protective parameter in terms of positive psychological outcomes in women with endometriosis. The results of this study may help to identify women at risk for adverse mental health outcomes and should encourage healthcare practitioners to establish strategies for the reduction of negative psychological and psychiatric impacts on patients with endometriosis

MYCN recruits the nuclear exosome complex to RNA polymerase II to prevent transcription-replication conflicts

The MYCN oncoprotein drives the development of numerous neuroendocrine and pediatric tumors. Here we show that MYCN interacts with the nuclear RNA exosome, a 3'-5' exoribonuclease complex, and recruits the exosome to its target genes. In the absence of the exosome, MYCN-directed elongation by RNA polymerase II (RNAPII) is slow and non-productive on a large group of cell-cycle-regulated genes. During the S phase of MYCN-driven tumor cells, the exosome is required to prevent the accumulation of stalled replication forks and of double-strand breaks close to the transcription start sites. Upon depletion of the exosome, activation of ATM causes recruitment of BRCA1, which stabilizes nuclear mRNA decapping complexes, leading to MYCN-dependent transcription termination. Disruption of mRNA decapping in turn activates ATR, indicating transcription-replication conflicts. We propose that exosome recruitment by MYCN maintains productive transcription elongation during S phase and prevents transcription-replication conflicts to maintain the rapid proliferation of neuroendocrine tumor cells

Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism

GBA1 mutations cause Gaucher’s disease and are the strongest risk factor for Parkinson’s disease. Using stable cell lines and patient iPSCs, the authors show mitochondrial localization of GBA1, which may affect neurodegenerative disease risk

Try, test and learn evaluation - interim report

This Interim Report of the Try, Test and Learn (TTL) Fund evaluation commissioned by the Australian Department of Social Services focusses on 14 tranche 1 TTL projects. A second tranche of TTL projects started one year later. The evaluation methodology follows an embedded mixed methods research design, integrating qualitative methods into a quasi-experimental design. This Interim Report assesses the establishment of the TTL Fund and the progress of TTL project implementation using 1 January 2018 – 30 June 2019 quantitative administrative data, 14 group interviews with tranche 1 project service providers and their available progress reports. It presents initial descriptive outcomes and comments on the adequacy of the administrative data for answering the evaluation questions