Leigh Syndrome Animal Model Service

Leigh syndrome animal models are genetically engineered preclinical systems that recapitulate the core neurological and metabolic features of the human disease. At Protheragen, we specialize in creating precise genetically engineered animal models to accelerate preclinical research into potential treatments for Leigh syndrome. Our expertise ensures our clients receive the most reliable and relevant support for their research, accelerating their drug development journey.

Introduction to Leigh Syndrome Animal Models

Leigh syndrome animal models are preclinical research tools primarily developed through genetic engineering to disrupt nuclear or mitochondrial genes critical for oxidative phosphorylation, such as Surf1, Ndufs4, and Ndufv1. These models are designed to recapitulate the characteristic neurological and metabolic features of the disorder, including progressive neurodegeneration, lactic acidosis, and failure to thrive. Serving as vital platforms for pathomechanism investigation, they enable detailed study of energy deficiency in neural tissues and provide essential systems for evaluating potential therapeutic interventions.

Fig.1 The Leigh syndrome mouse model can be rescued by interventions that normalize brain hyperoxia but not HIF activation. (Jain I H, Zazzeron L, et al., 2019)

Our Services

As a leading preclinical research services provider, Protheragen offers specialized and highly accurate animal model development services for Leigh syndrome research. Our team leverages advanced genetic engineering technologies to create genetically precise models that faithfully recapitulate key pathological features of the disorder, such as mitochondrial dysfunction, neurodegeneration, and bioenergetic deficits.

Animal Models of Leigh Syndrome

Featured Animal Models

Case Study-Transgenic ATP6 (A6) Mouse Model

Model Introduction

This case study describes the generation and phenotypic characterization of the transgenic ATP6 (A6) mouse model, a specialized model for Leigh syndrome. This severe neurological disorder is frequently caused by mitochondrial DNA mutations, such as the human m.8993T>G mutation in the ATP6 gene, which compromises mitochondrial complex V function. Our model utilizes a transgenic approach to stably introduce this pathogenic human gene into the mouse genome, enabling the study of progressive neurodegenerative features associated with the disease.

Methodology

• Animal Model: Transgenic ATP6 (A6) mice on a C57BL/6J background and wild-type (WT) controls.
• Modeling Method: The model was created by microinjecting AAV2 vectors carrying the human ATP6 gene with the pathogenic m.8993T>G mutation into mouse blastocysts to achieve germline transmission. The transgene was fused to a cytochrome c oxidase subunit 8 (COX8) mitochondrial targeting sequence (MTS) to ensure proper localization of the mutant protein within the mitochondrial inner membrane.
• Phenotypic Analysis Methods: A multi-system approach was employed, including:
  • Retinal Histology: Measurement of outer nuclear layer (ONL) and inner nuclear layer (INL) thickness.
  • Neuropathology: Quantification of brain lesion burden.
  • Ultrastructural Analysis: Assessment of mitochondrial cristae morphology in neurons via electron microscopy.

Phenotypic Analysis & Results

Comprehensive analysis confirmed that the A6 mice recapitulate the hallmark multisystemic pathologies of Leigh syndrome.

• Retinal Degeneration: The ONL and/or INL thickness of the retina in A6 mice was significantly reduced compared to WT mice (Fig.2A), indicating progressive photoreceptor and neuronal loss.
• Central Nervous System Lesions: Quantification of lesions in the brains of A6 mice shows a two-fold increase relative to normal brain (Fig.2B), demonstrating significant neuronal degeneration.
• Mitochondrial Ultrastructural Defects: Mitochondrial cristae in the affected regions of A6 mouse neurons are two times wider than adjacent normal cristae (Fig.2C), providing direct structural evidence of mitochondrial dysfunction.

Fig.2 Multisystemic pathological manifestations in transgenic ATP6 (A6) mice. (A) Retinal layer thickness is significantly reduced. (B) Brain lesion is markedly increased. (C) Mitochondrial cristae in neurons are pathologically widened. Data are presented as mean ± SD (n=5-8). **p < 0.01, ***p < 0.001 vs. WT.

Conclusion

This case study validates the transgenic ATP6 (A6) mouse as a robust and relevant model for Leigh syndrome research. The model successfully recapitulates the core triad of disease pathology: retinal degeneration, central nervous system lesions, and definitive mitochondrial ultrastructural abnormalities. This comprehensive phenotypic recapitulation makes the A6 model an invaluable tool for:

• Investigating Disease Mechanisms: Elucidating the pathophysiological link between mitochondrial complex V deficiency and progressive neurodegeneration.
• Therapeutic Development: Evaluating the efficacy of novel treatments targeting mitochondrial function, including small molecule therapies and gene-based interventions.
• Biomarker Discovery: Identifying and validating structural and imaging biomarkers for disease progression and therapeutic response.

Contact Us

At Protheragen, we are committed to developing comprehensive Leigh syndrome animal models to advance therapeutic development through integrated pharmacodynamics (PD), pharmacokinetics (PK), and toxicology studies. Our validated models serve as critical tools for evaluating drug efficacy, metabolic stability, and safety profiles, providing robust preclinical data to support regulatory submissions. If you are interested in our animal model development services, please do not hesitate to contact us for more details and quotation information.

Reference

1. Jain I H, Zazzeron L, Goldberger O, et al. Leigh syndrome mouse model can be rescued by interventions that normalize brain hyperoxia, but not HIF activation[J]. Cell metabolism, 2019, 30(4): 824-832. e3.