Prevalence of Aggressive Behavior and Associated Factors among Patients with Schizophrenia Attending at Amanuel Mental Specialized Hospital Addis Ababa, Ethiopia

Background: Mental illness and aggression are often seen as inextricably linked, creating a harsh stigma for patients and, at times, an uncomfortable environment for mental health professional. There is a growing body of evidence on aggressive behavior towards others by people with schizophrenia. Thus, this study was designed to assess the prevalence of aggressive behavior and associated factors among schizophrenia patients attending at Amanuel Mental Specialized Hospital.Method: Institutional based cross-sectional study was employed on 403 patients with schizophrenia attending at outpatient department of Amanuel Mental Specialized Hospital from May 1 to 31 2017. A systematic random sampling technique was used. Aggressive behavior was assessed by using Modified Overt Aggression Scale.The coded Data was checked, cleaned and entered into EPI-INFO version 3.5.3 and then exported into SPSS version 20 for analysis. Multivariable binary logistic regression was applied to find out the explanatory variables associated with aggressive behavior. Significance was declared at p-value <0.05.Results: The prevalence of aggression in this study was 107 (26.55%) by using Modified Overt Aggression Scale. Of 107 aggressive patients, 81(75.7%) and 26(24.3%) were male and female, respectively. The commonest associated factors for aggressive behavior include male [AOR=2.61, 95%CI (1.21, 5.61)], unemployment [AOR=8.03, 95%CI (3.08, 25.95)], previous history of aggression [AOR=6.22, 95%CI (2.75, 14.10)], Psychotic symptoms [AOR=8.12, (3.11, 21.14)], poor social support [AOR=3.11, 95%CI (1.35, 7.17)] and alcohol use [AOR=2.40, 95%CI (1.02, 5.66)].Conclusion: The prevalence of aggression behavior was found to be slightly high. Occupation, diagnosis episode of schizophrenia, previous history of aggression, types of drug taken, psychotic symptom, social support and alcohol use were found to be significantly associated with aggressive behavior. Clinicians should consider early detection& management of aggression. Keywords: Aggression, Schizophrenia, Violence DOI: 10.7176/JMPB/73-02 Publication date: January 31st 202

KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1

The mechanistic target of rapamycin complex 1 kinase (mTORC1) is a central regulator of cell growth that responds to diverse environmental signals and is deregulated in many human diseases, including cancer and epilepsy1–3. Amino acids are a key input, and act through the Rag GTPases to promote the translocation of mTORC1 to the lysosomal surface, its site of activation4. Multiple protein complexes regulate the Rag GTPases in response to amino acids, including GATOR1, a GTPase activating protein for RagA, and GATOR2, a positive regulator of unknown molecular function. Here, we identify a four-membered protein complex (KICSTOR) composed of the KPTN, ITFG2, C12orf66, and SZT2 gene products as required for amino acid or glucose deprivation to inhibit mTORC1 in cultured cells. In mice lacking SZT2, mTORC1 signaling is increased in several tissues, including in neurons in the brain. KICSTOR localizes to lysosomes; binds to GATOR1 and recruits it, but not GATOR2, to the lysosomal surface; and is necessary for the interaction of GATOR1 with its substrates, the Rag GTPases, and with GATOR2. Interestingly, several KICSTOR components are mutated in neurological diseases associated with mutations that lead to hyperactive mTORC1 signaling5–10. Thus, KICSTOR is a lysosome-associated negative regulator of mTORC1 signaling that, like GATOR1, is mutated in human disease11,12

Regulation of amino acid transport across the lysosomal surface by the mTORC1 pathway

Multicellular eukaryotes readily adjust their growth in response to environmental cues. A central nutrient sensing pathway crucial for this process requires the mechanistic target of rapamycin complex 1 (mTORC1), which integrates various inputs such as amino acids, growth factor signaling and energy levels. Amino acids promote the localization of mTORC1 to the lysosomal surface, where it can then be activated in response to growth factor availability. While the Rag GTPases mediate the recruitment of mTORC1 to the lysosomal surface, they also have a mutually exclusive and nutrient regulated interaction with SLC38A9, a lysosomal amino acid transporter. How the mutually exclusive mTORC1-Rag and the SLC38A9-Rag interaction is achieved and how it alters the function of each component is not completely understood. We found the Rag GTPases are necessary to promote SLC38A9 transport independent of mTORC1 kinase activity. Moreover, we attained the structures of Raptor-Rag-Ragulator and SLC38A9-Rag-Ragulator at 3.2 Å and 3.6 Å resolutions, respectively, and generated separation of function mutants of RagA. Using these constructs, we show that perturbation of Rag GTPase binding to SLC38A9, but not mTORC1, causes the accumulation of a distinct set of non-polar, mostly essential amino acids (Tyrosine, Leucine, Phenylalanine, and Isoleucine). We also show that “inactive” Rags, competent to bind SLC38A9, promote its transport activity in proteoliposomes reconstituted with wild-type SLC38A9. We believe the purpose of this regulation is to efflux amino acids from the lysosome during starvation. Overall, we identified the mechanism by which mTORC1 regulates the efflux of essential amino acids from lysosomes to be through the Rag-Ragulator complex. This work ascribes an alternative function to the Rag-Ragulator complex independent of its ability to convey the availability of nutrients to mTORC1. Furthermore, we show this direct gating mechanism plays a role in regulating the efflux of essential amino acids from lysosomes of mouse hepatocytes in-vivo during periods of starvation and refeeding. Thus, the studies described in this thesis provide new insights to the role of the Rag GTPases by genetic, biochemical, and structural techniques. Further mechanistic insights into Rag-Ragulator binding to SLC38A9 will reveal how the Rag GTPases regulate its transport function, along with that of other interactors, in various physiological contexts.Ph.D

Structural basis for the docking of mTORC1 on the lysosomal surface

© 2019 American Association for the Advancement of Science. All rights reserved. The mTORC1 (mechanistic target of rapamycin complex 1) protein kinase regulates growth in response to nutrients and growth factors. Nutrients promote its translocation to the lysosomal surface, where its Raptor subunit interacts with the Rag guanosine triphosphatase (GTPase)-Ragulator complex. Nutrients switch the heterodimeric Rag GTPases among four different nucleotide-binding states, only one of which (RagA/B•GTP-RagC/D•GDP) permits mTORC1 association. We used cryo-electron microscopy to determine the structure of the supercomplex of Raptor with Rag-Ragulator at a resolution of 3.2 angstroms. Our findings indicate that the Raptor a-solenoid directly detects the nucleotide state of RagA while the Raptor "claw" threads between the GTPase domains to detect that of RagC. Mutations that disrupted Rag-Raptor binding inhibited mTORC1 lysosomal localization and signaling. By comparison with a structure of mTORC1 bound to its activator Rheb, we developed a model of active mTORC1 docked on the lysosome