Hereditary early-onset Parkinsonism : the role of the FBXO7 protein

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, which affects ~1-2% of the population above the age of 60 years old. We identified pathogenic mutations in the FBXO7 gene in two families with early-onset, progressive parkinsonism and pyramidal tract dysfunctions. This finding provided the conclusive evidence that FBXO7 is the disease-causing gene in this newly-identified autosomal recessive form, which we termed PARK15. Very little was known about the two protein isoforms, which are predicted to be encoded by FBXO7, and nothing was known about their expression in the human brain. Here, we demonstrated the expression of these proteins in normal human cells and the consequences of mutations in cells derived from PARK15 patients. In parallel with the above-mentioned in vitro experiments, we also generated the first in vivo model of PARK15 by transient, morpholino-mediated knockdown of the homologous gene Fbxo7 in zebrafish. This model displayed both pathologic and behavioural 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. Moreover, the expression of FBXO7 proteins in the brain of normal human subjects and of PD patients was investigated. We observed widespread neuronal FBXO7 immunoreactivity throughout the brain regions, of note, the FBXO7 immunoreactivity was also detected in the Lewy bodies and Lewy neuritis, suggesting a role for FBXO7 proteins in the pathogenesis of Lewy-body pathology in the common (non-Mendelian) forms of synucleinopathies.

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