FBXO7 Immunoreactivity in α-Synuclein—Containing Inclusions in Parkinson Disease and Multiple System Atrophy

Abstract

Mutations in the gene encoding the F-box only protein 7 (FBXO7) cause PARK15, an autosomal recessive form of juvenile parkinsonism. Although the brain pathology in PARK15 patients remains unexplored, in vivo imaging displays severe loss of nigrostriatal dopaminergic terminals. Understanding the pathogenesis of PARK15 might therefore illuminate the mechanisms of the selective dopaminergic neuronal degeneration, which could also be important for understanding idiopathic Parkinson disease (PD). The expression of FBXO7 in the human brain remains poorly characterized, and its expression in idiopathic PD and different neurodegenerative diseases has not been investigated. Here, we studied FBXO7 protein expression in brain samples of normal controls (n = 9) and from patients with PD (n = 13), multiple system atrophy (MSA) (n = 5), Alzheimer disease (AD) (n = 5), and progressive supranuclear palsy (PSP) (n = 5) using immunohistochemistry with 2 anti-FBXO7 antibodies. We detected widespread brain FBXO7 immunoreactivity, with the highest levels in neurons of the cerebral cortex, putamen, and cerebellum. There were no major differences between normal and PD brains overall, but FBXO7 immunoreactivity was detected in large proportions of α-synuclein-positive inclusions (Lewy bodies, Lewy neurites, glial cytoplasmic inclusions), where it colocalized with α-synuclein in PD and MSA cases. By contrast, weak FBXO7 immunoreactivity was occasionally detected in tau-positive inclusions in AD and PSP. These findings suggest a role for FBXO7 in the pathogenesis of the synucleinopathies.

A new F‐box protein 7 gene mutation causing typical Parkinson's disease

“…The FBXO7 gene encodes an E3 ligase, involved in the ubiquitin‐proteasome pathway of protein degradation, which plays a role in the pathogenesis of neurodegenerative diseases, and pathogenic FBXO7 gene mutations are likely to induce protein dysfunction leading to deficient ubiquitination of substrates. A recent study suggested a role for the FBXO7 protein in the pathogenesis also of common forms of synucleinopathies, such as idiopathic Parkinson's disease (PD) and MSA . In this study, we report on a Turkish family with 2 affected sibs from consanguineous parents carrying a new homozygous p.L34R FBXO7 mutation.…”

A new Turkish family with homozygous FBXO7 truncating mutation and juvenile atypical parkinsonism

“…Modeling the loss of FBXO7 function in Zebrafish recapitulated cardinal features of the human disease, including loss of dopaminergic neurons and dopamine-dependent locomotor deficit [8]. Last, there is evidence that the FBXO7 protein accumulates in the alpha-synuclein-positive inclusions in the patients with classical late-onset Parkinson's disease and in those with multiple system atrophy, suggesting a broader involvement in the pathogenesis of synucleinopathies [9].…”

α-Synuclein and Lewy pathology in Parkinson's disease

“…EIF4G1 or DNAJC13 immunoreactivity in Lewy bodies has only been examined in postmortem samples from patients with Parkinson's disease with corresponding gene mutations; less than 50% of Lewy bodies were found to be immunoreactive for DNAJC13 [33] and most were nonimmunoreactive for EIF4G1 [34]. Among the proteins associated with autosomal recessive parkinsonism, parkin, PINK1, DJ-1 (reviewed in [24]), ATP13A2 [35], and FBXO7 [36] have all been reported to localize to Lewy bodies. Glucocerebrosidase, the protein encoded by the GBA gene, was found to be present in an average of 75% of Lewy bodies in patients with GBA mutations and concomitant parkinsonism [37].…”