Decreased BDNF Levels Are a Major Contributor to the Embryonic Phenotype of Huntingtin Knockdown Zebrafish

Abstract

Huntington's disease (HD) is an autosomal dominant, neurodegenerative condition caused by a CAG trinucleotide repeat expansion that is translated into an abnormally long polyglutamine tract in the protein huntingtin. Genetic and transgenic studies suggest that the mutation causes disease predominantly via gain-of-function mechanisms. However, loss of normal huntingtin function resulting from the polyglutamine expansion might also contribute to the pathogenesis of HD. Here, we have studied the effects of huntingtin knockdown in zebrafish using morpholino antisense oligonucleotides, as its huntingtin orthologue has 70% amino acid identity with the human protein. Reduced huntingtin levels did not impact on gastrulation and early development, but caused massive apoptosis of neuronal cells by 24 hpf. This was accompanied by impaired neuronal development, resulting in small eyes and heads and enlargement of brain ventricles. Older huntingtin knockdown fish developed lower jaw abnormalities with most branchial arches missing. Molecular analysis revealed that BDNF expression was reduced by ϳ50%. Reduction of BDNF levels by injection of a BDNF morpholino resulted in phenotypes very similar to those seen in huntingtin knockdown zebrafish. The phenotypes of both huntingtin-and BDNF-knockdown zebrafish showed significant rescue when treated with exogenous BDNF protein. This underscores the physiological importance of huntingtin as a regulator of BDNF production and suggests that loss of BDNF is a major cause of the developmental abnormalities seen with huntingtin knockdown in zebrafish. Increasing BDNF expression may represent a useful strategy for Huntington's disease treatment.

Nucleoporin 62-Like Protein Activates Canonical Wnt Signaling through Facilitating the Nuclear Import of β-Catenin in Zebrafish

“…Wnt/␤-catenin signaling is known to play a key role in the regulation of embryogenesis and oncogenesis (85)(86)(87). In zebrafish, activation of the Wnt/␤-catenin pathway facilitates cardiac differentiation before gastrulation but perturbs it at later stages (45).…”

The developmental neurotoxicity of polybrominated diphenyl ethers: Effect of DE‐71 on dopamine in zebrafish larvae

“…In zebrafish embryos/larvae, bdnf is critical in neuronal development, with bdnf knockdown causing severe brain atrophy, with experimental zebrafish larvae lacking most of the neurites [38]. Thus, downregulation of bdnf observed in our study might also contribute to impaired DA neurodevelopment and decreased DA content.…”

Developing ‘integrative’ zebrafish models of behavioral and metabolic disorders

“…↓ Food consumption After feeding, bdnf expression increases; knockdown decreases locomotor activity and shows Huntington-like symptoms (zebrafish) [295] Corticotropin releasing hormone (CRH) ↓ Food consumption ICV administration suppresses food consumption and increases anxiety-like behavior and locomotion (goldfish) [206,296] Octadecaneuropeptide (ODN) ↓ Food consumption and ↑ Locomotion ICV administration suppresses food consumption and locomotion (goldfish) [297] Pituitary adenylatecyclase-activating polypeptide (PACAP)…”