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miR143-3p-Mediated NRG-1-Dependent Mitochondrial Dysfunction Contributes to Olanzapine Resistance in Refractory
Jing Sun1, Xiaoya Zhang2, Qijie Cong2
1Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China; Neurobiology & Mitochondrial Key Laboratory, School of Pharmacy, Jiangsu University, Zhenjiang, China.
Background:
Olanzapine is an effective antipsychotic medication for treatment-resistant schizophrenia (TRS); however, the therapeutic effectiveness of olanzapine has been found to vary in individual patients. It is imperative to unravel its resistance mechanisms and find reliable targets to develop novel precise therapeutic strategies.
Methods:
Unbiased RNA sequencing analysis was performed using homogeneous populations of neural stem cells derived from induced pluripotent stem cells in 3 olanzapine responder (reduction of Positive and Negative Syndrome Scale score ≥25%) and 4 nonresponder (reduction of Positive and Negative Syndrome Scale score <25%) inpatients with TRS. We also used a genotyping study from patients with TRS to assess the candidate genes associated with the olanzapine response. CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9-mediated genome editing, neurologic behavioral tests, RNA silencing, and microRNA sequencing were used to investigate the phenotypic mechanisms of an olanzapine resistance gene in patients with TRS.
Results:
Neuregulin-1 (NRG-1) deficiency-induced mitochondrial dysfunction is associated with olanzapine treatment outcomes in TRS. NRG-1 knockout mice showed schizophrenia-relevant behavioral deficits and yielded olanzapine resistance. Notably, miR143-3p is a critical NRG-1 target related to mitochondrial dysfunction, and miR143-3p levels in neural stem cells associate with severity to olanzapine resistance in TRS. Meanwhile, olanzapine resistance in NRG-1 knockout mice could be rescued by treatment with miR143-3p agomir via intracerebral injection.
Conclusions:
Our findings provide direct evidence of olanzapine resistance resulting from NRG-1 deficiency-induced mitochondrial dysfunction, and they link olanzapine resistance and NRG-1 deficiency-induced mitochondrial dysfunction to an NRG-1/miR143-3p axis, which constitutes a novel biomarker and target for TRS.
Insights
Neuregulin-1 (NRG-1) deficiency causes mitochondrial dysfunction, leading to olanzapine resistance in treatment-resistant schizophrenia (TRS). Restoring miR143-3p levels can overcome this resistance, offering a new therapeutic target for TRS.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Olanzapine is effective for treatment-resistant schizophrenia (TRS), but patient responses vary.
- Understanding olanzapine resistance mechanisms is crucial for developing precise therapeutic strategies.
Purpose of the Study:
- To investigate the molecular mechanisms underlying olanzapine resistance in patients with TRS.
- To identify potential biomarkers and therapeutic targets for improving olanzapine treatment outcomes in TRS.
Main Methods:
- RNA sequencing and genotyping were performed on neural stem cells from TRS patients (responders and non-responders).
- CRISPR/Cas9 genome editing, behavioral tests, and RNA silencing were used to study olanzapine resistance genes.
- MicroRNA sequencing identified miR143-3p as a key regulator in the identified pathway.
Main Results:
- Neuregulin-1 (NRG-1) deficiency-induced mitochondrial dysfunction is linked to olanzapine treatment outcomes in TRS.
- NRG-1 knockout mice exhibited schizophrenia-like behaviors and olanzapine resistance.
- miR143-3p is a critical target of NRG-1 involved in mitochondrial dysfunction and correlates with olanzapine resistance severity.
Conclusions:
- Olanzapine resistance in TRS is associated with NRG-1 deficiency and subsequent mitochondrial dysfunction.
- The NRG-1/miR143-3p axis represents a novel biomarker and therapeutic target for treatment-resistant schizophrenia.
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