Ataxia with giant axonopathy in Acbd5-deficient mice halted by adeno-associated virus gene therapy.

Autor:	Granadeiro L; Neurolipid 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.; Graduate Program in Molecular and Cell Biology, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, 4050-313 Porto, Portugal., Zarralanga VE; Neurolipid 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., Rosa R; Neurolipid 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., Franquinho F; Animal Facility, Instituto de Investigação e Inovação em Saúde da Universidade do Porto - i3S, 4200-135 Porto, Portugal., Lamas S; Animal Facility, Instituto de Investigação e Inovação em Saúde da Universidade do Porto - i3S, 4200-135 Porto, Portugal., Brites P; Neurolipid 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.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2024 Apr 04; Vol. 147 (4), pp. 1457-1473.
DOI:	10.1093/brain/awad407
Abstrakt:	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. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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