Efficient Neuroprotective Rescue of Sacsin-Related Disease Phenotypes in Zebrafish.

Abstract

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a multisystem hereditary ataxia associated with mutations in SACS, which encodes sacsin, a protein of still only partially understood function. Although mouse models of ARSACS mimic largely the disease progression seen in humans, their use in the validation of effective therapies has not yet been proposed. Recently, the teleost Danio rerio has attracted increasing attention as a vertebrate model that allows rapid and economical screening, of candidate molecules, and thus combines the advantages of whole-organism phenotypic assays and in vitro high-throughput screening assays. Through CRISPR/Cas9-based mutagenesis, we generated and characterized a zebrafish sacs-null mutant line that replicates the main features of ARSACS. The sacs-null fish showed motor impairment, hindbrain atrophy, mitochondrial dysfunction, and reactive oxygen species accumulation. As proof of principle for using these mutant fish in high-throughput screening studies, we showed that both acetyl-DL-leucine and tauroursodeoxycholic acid improved locomotor and biochemical phenotypes in sacs-/- larvae treated with these neuroprotective agents, by mediating significant rescue of the molecular functions altered by sacsin loss. Taken together, the evidence here reported shows the zebrafish to be a valuable model organism for the identification of novel molecular mechanisms and for efficient and rapid in vivo optimization and screening of potential therapeutic compounds. These findings may pave the way for new interventions targeting the earliest phases of Purkinje cell degeneration in ARSACS.

• Authors: Valentina Naef, Maria Marchese, Asahi Ogi, Gianluca Fichi, Daniele Galatolo, Rosario Licitra, Stefano Doccini, Tiziano Verri, Francesco Argenton, Federica Morani, Filippo M Santorelli
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 16 (Aug 05 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34445111 (Publication Type: Journal Article)

Chemical References

• Heat-Shock Proteins
• Neuroprotective Agents

Topics

• Animals
• Animals, Genetically Modified (metabolism)
• Ataxia (metabolism)
• Cerebellar Ataxia (metabolism)
• Disease Models, Animal
• Disease Progression
• Heat-Shock Proteins (metabolism)
• Muscle Spasticity (metabolism)
• Mutation (genetics)
• Neuroprotective Agents (metabolism)
• Phenotype
• Purkinje Cells (metabolism)
• Spinocerebellar Ataxias (congenital, metabolism)
• Zebrafish (metabolism)