RESUMO
Current approaches to the treatment of schizophrenia have mainly focused on the protein-coding part of the genome; in this context, the roles of microRNAs have received less attention. In the present study, we analyze the microRNAome in the blood and postmortem brains of schizophrenia patients, showing that the expression of miR-99b-5p is downregulated in both the prefrontal cortex and blood of patients. Lowering the amount of miR-99b-5p in mice leads to both schizophrenia-like phenotypes and inflammatory processes that are linked to synaptic pruning in microglia. The microglial miR-99b-5p-supressed inflammatory response requires Z-DNA binding protein 1 (Zbp1), which we identify as a novel miR-99b-5p target. Antisense oligonucleotides against Zbp1 ameliorate the pathological effects of miR-99b-5p inhibition. Our findings indicate that a novel miR-99b-5p-Zbp1 pathway in microglia might contribute to the pathogenesis of schizophrenia.
Assuntos
MicroRNAs , Esquizofrenia , Animais , Humanos , Camundongos , Microglia/metabolismo , MicroRNAs/metabolismo , Proteínas de Ligação a RNA/metabolismo , Esquizofrenia/genéticaRESUMO
BACKGROUND: Research on people deprived of liberty raises serious questions, especially concerning behavioral genetic studies. QUESTION: Does including criminally detained patients with mental disorders in genetic studies lead to a gain of new knowledge and can this be ethically and legally justified? METHOD: Evaluation of existing literature and interdisciplinary reflection. RESULTS: After a review of research ethics and legal norms, we consider the benefits and risks of behavioral genetic research, taking the unique situation of test persons deprived of their liberty into account. The fundamental right to freedom of research also justifies foundational research in forensic psychiatry and psychotherapy. The possible future benefits of improving treatment plans must be weighed against the risks resulting from potential data leaks and inappropriate public reception of research results. Then we analyze possible threats to voluntary and informed consent to study participation in more detail by the ethical concept of vulnerability. Alongside problems with grasping complex issues, above all dependencies and power dynamics in the correctional system play a pivotal role. Recommendations on the ethical and legal inclusion of this study population are given. CONCLUSION: Including criminally detained study participants can be ethically and legally justified when autonomous consent is supported by specific organizational and legal procedures and measures, for example via a clear professional and organizational separation of correction and research.