Abstract
Recessive mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, a Mendelian form of early-onset, levodopa-responsive parkinsonism with severe loss of nigrostriatal dopaminergic neurons. However, the function of the protein encoded by FBXO7, and the pathogenesis of PARK15 remain unknown. No animal models of this disease exist. Here, we report the generation of a vertebrate model of PARK15 in zebrafish. We first show that the zebrafish Fbxo7 homolog protein (zFbxo7) is expressed abundantly in the normal zebrafish brain. Next, we used two zFbxo7-specific morpholinos (targeting protein translation and mRNA splicing, respectively), to knock down the zFbxo7 expression. The injection of either of these zFbxo7-specific morpholinos in the fish embryos induced a marked decrease in the zFbxo7 protein expression, and a range of developmental defects. Furthermore, whole-mount in situ mRNA hybridization showed abnormal patterning and significant decrease in the number of diencephalic tyrosine hydroxylase-expressing neurons, corresponding to the human nigrostriatal or ventral tegmental dopaminergic neurons. Of note, the number of the dopamine transporter-expressing neurons was much more severely depleted, suggesting dopaminergic dysfunctions earlier and larger than those due to neuronal loss. Last, the zFbxo7 morphants displayed severe locomotor disturbances (bradykinesia), which were dramatically improved by the dopaminergic agonist apomorphine. The severity of these morphological and behavioral abnormalities correlated with the severity of zFbxo7 protein deficiency. Moreover, the effects of the co-injection of zFbxo7- and p53-specific morpholinos were similar to those obtained with zFbxo7-specific morpholinos alone, supporting further the contention that the observed phenotypes were specifically due to the knock down of zFbxo7. In conclusion, this novel vertebrate model reproduces pathologic and behavioral hallmarks of human parkinsonism (dopaminergic neuronal loss and dopamine-dependent bradykinesia), representing therefore a valid tool for investigating the mechanisms of selective dopaminergic neuronal death, and screening for modifier genes and therapeutic compounds.
Highlights
Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease, is characterized by the progressive loss of nigrostriatal dopaminergic neurons, and the formation of alpha-synuclein-containing protein aggregates, termed Lewy bodies, in surviving neurons [1]
We recently reported that two protein isoforms are expressed from the F-box only protein 7 (FBXO7) gene, and that PARK15 patients display a severe depletion of the longer isoform, which normally localizes in the cell nucleus
Its 1452-nucleotide transcript is predicted to encode a protein of 483 amino acids, which displays the same domain organization as the human longer FBXO7 isoform 1, and shows an overall 40% amino acid identity, rising to 65% identity and 78% similarity in the F-box domain (Figure 1A)
Summary
Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease, is characterized by the progressive loss of nigrostriatal dopaminergic neurons, and the formation of alpha-synuclein-containing protein aggregates, termed Lewy bodies, in surviving neurons [1]. Whether the mutations in the different forms of monogenic parkinsonisms converge on the same or different cellular pathways remains currently unclear. Understanding the mechanisms of these Mendelian parkinsonisms might provide important clues into the pathways leading to the degeneration of the dopaminergic neurons, which might be involved in the common forms of PD. PARK15 patients display dramatic loss of nigrostriatal dopaminergic neurons, and they suffer from juvenile parkinsonism, with varying degrees of pyramidal disturbances. The parkinsonism displays a good response to levodopa therapy, indicating the relative integrity of the striatal neuronal circuitry acting downstream to the nigrostriatal dopaminergic defect [7,8]
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