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Published on: August 25, 2017
Ataxia with giant axonopathy in Acbd5-deficient mice halted by adeno-associated virus gene therapy
Luis Granadeiro1,2, Violeta Enríquez Zarralanga1, Ricardo Rosa1
1Neurolipid Biology, Instituto de Investigação e Inovação em Saúde da Universidade do Porto - i3S and Instituto de Biologia Molecular e Celular - IBMC, 4200-135 Porto, Portugal.
Abstract:
Acyl-CoA binding domain containing 5 (ACBD5) is a critical player in handling very long chain fatty acids (VLCFA) en route for peroxisomal β-oxidation. Mutations in ACBD5 lead to the accumulation of VLCFA and patients present retinal dystrophy, ataxia, psychomotor delay and a severe leukodystrophy. Using CRISPR/Cas9, we generated and characterized an Acbd5 Gly357* mutant allele. Gly357* mutant mice recapitulated key features of the human disorder, including reduced survival, impaired locomotion and reflexes, loss of photoreceptors, and demyelination. The ataxic presentation of Gly357* mice involved the loss of cerebellar Purkinje cells and a giant axonopathy throughout the CNS. Lipidomic studies provided evidence for the extensive lipid dysregulation caused by VLCFA accumulation. Following a proteomic survey, functional studies in neurons treated with VLCFA unravelled a deregulated cytoskeleton with reduced actin dynamics and increased neuronal filopodia. We also show that an adeno-associated virus-mediated gene delivery ameliorated the gait phenotypes and the giant axonopathy, also improving myelination and astrocyte reactivity. Collectively, we established a mouse model with significance for VLCFA-related disorders. The development of relevant neuropathological outcomes enabled the understanding of mechanisms modulated by VLCFA and the evaluation of the efficacy of preclinical therapeutic interventions.
Insights
Acyl-CoA binding domain containing 5 (ACBD5) mutations cause very long chain fatty acid (VLCFA) accumulation, leading to severe neurological and retinal diseases. A new Acbd5 mutant mouse model effectively recapitulates these human disorders, aiding research into VLCFA-related conditions.
Area of Science:
- Biochemistry
- Neuroscience
- Genetics
Background:
- Acyl-CoA binding domain containing 5 (ACBD5) is crucial for very long chain fatty acid (VLCFA) metabolism and peroxisomal β-oxidation.
- ACBD5 mutations result in VLCFA accumulation, causing retinal dystrophy, ataxia, psychomotor delay, and leukodystrophy in humans.
Purpose of the Study:
- To generate and characterize a mouse model mimicking human ACBD5-related disorders.
- To investigate the neuropathological mechanisms underlying VLCFA accumulation.
- To evaluate potential therapeutic interventions for VLCFA-related diseases.
Main Methods:
- CRISPR/Cas9 gene editing to create an Acbd5 Gly357* mutant mouse allele.
- Phenotypic analysis including locomotion, reflexes, survival, and histopathology (retina, cerebellum, CNS).
- Lipidomic and proteomic analyses, in vitro neuronal studies, and adeno-associated virus (AAV)-mediated gene therapy.
Main Results:
- Acbd5 Gly357* mice exhibited reduced survival, impaired motor function, photoreceptor loss, demyelination, Purkinje cell loss, and giant axonopathy.
- Lipidomic studies confirmed widespread lipid dysregulation due to VLCFA accumulation.
- VLCFA exposure in neurons led to cytoskeletal deregulation, reduced actin dynamics, and increased filopodia; AAV gene delivery improved phenotypes and myelination.
Conclusions:
- The Acbd5 Gly357* mouse model accurately recapitulates key features of human ACBD5-related disorders.
- This model facilitates understanding of VLCFA-induced neuropathology, including cytoskeletal defects.
- The study demonstrates the therapeutic potential of gene delivery for VLCFA-related leukodystrophies.
