Biology subjects

Al Rawi, S.

Publications and source records attributed to Al Rawi, S..

3 recordsLinked to original sources

bioRxiv2024

Restoration of Fbxo7 expression in dopaminergic neurons restores tyrosine hydroxylase in a mouse model of Parkinson's disease

Mutations in FBXO7 are linked to an atypical parkinsonism. Conditional knock out (KO) of Fbxo7 in dopaminergic neurons in a mouse model caused a neurodegenerative phenotype, including a significant reduction in striatal TH staining at 6 weeks of age and a significant loss of dopaminergic neurons in the SNpc. To test whether re-expression of Fbxo7 could act as a treatment to prevent or restore TH expression in the striatum in this model, we used a rAAV vector to deliver murine Fbxo7 and a mRuby fluorescent marker to dopaminergic neurons. We found that Fbxo7 expression, both before and after the TH loss, restored its expression in the striatum and nucleus accumbens in the mouse. This study therefore highlights that Fbxo7 is important for the integrity and persistence of the dopaminergic nigrostriatal pathway in the mammalian brain, which could be of relevance to Parkinsons disease with therapeutic implications.

neuroscience↗

bioRxiv2021

Study of an FBXO7 patient mutation reveals Fbxo7 and PI31 co-regulate proteasomes and mitochondria

Mutations in FBXO7 have been discovered associated with an atypical parkinsonism. We report here a new homozygous missense mutation in a paediatric patient that causes an L250P substitution in the dimerization domain of Fbxo7. This alteration selectively ablates the Fbxo7-PI31 interaction and causes a significant reduction in Fbxo7 and PI31 levels in patient cells. Consistent with their association with proteasomes, L250P patient fibroblasts have reduced proteasome activity and proteasome subunits. We also show PI31 interacts directly with the MiD49/51 fission adaptor proteins, and unexpectedly, PI31 acts as an adaptor enabling SCFFbxo7 ligase to ubiquitinate MiD49. Thus, the L250P mutation changes the function of Fbxo7 by altering its substrate repertoire. Although MiD49/51 expression was reduced in L250P patient cells, there was no effect on the mitochondrial network. However, patient cells had higher levels of ROS and reduced viability under stress. Our study shows that Fbxo7 and PI31 affect each others functions in regulating both proteasomal and mitochondrial function and demonstrate a new function for PI31, as an adaptor for the SCFFbxo7 E3 ubiquitin ligase.

neuroscience↗

bioRxiv2019

A conserved requirement for Fbxo7 during male germ cell cytoplasmic remodelling

Summary statementFbxo7 is the substrate-recognition subunit of an SCF-type ubiquitin E3 ligase complex. It has physiologically important functions in regulating mitophagy, proteasome activity and the cell cycle in multiple cell types, like neurons, lymphocytes and erythrocytes. Here we show that in addition to the previously-known Parkinsonian and haematopoietic phenotypes, Fbxo7-deficient male mice are completely sterile. In these males, despite successful meiosis, nuclear elongation and eviction of histones from chromatin, the developing spermatids are phagocytosed by Sertoli cells during late spermiogenesis, as the cells undergo cytoplasmic remodelling. Surprisingly, despite the loss of all germ cells, there was no evidence of the symplast formation and cell sloughing that is typically associated with spermatid death in other mouse sterility models, suggesting that novel cell death and/or cell disposal mechanisms may be engaged in Fbxo7-deficient males. Mutation of the Drosophila Fbxo7 orthologue, nutcracker (ntc) was previously shown to cause sterility at a similar stage of germ cell development, indicating that the requirement for Fbxo7 is conserved. The ntc phenotype was attributed to proteasome mis-regulation via an interaction with the proteasome regulator, DmPI31. Our data suggest rather that in mice, the requirement for Fbxo7 is either independent of its interaction with PI31, or relates specifically to cytoplasmic proteasome activity during spermiogenesis.

developmental biology↗