Structure and Function of Fbxo7/PARK15 in Parkinson's Disease

Randle, Suzanne J.; Laman, Heike

doi:10.2174/1389203717666160311121433

Cited by 22 publications

(26 citation statements)

References 77 publications

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“…In this regard, biochemical findings in Drosophila showed that overexpression of wild-type FBXO7 suppresses mitochondrial disruption and also neurodegeneration process in PARKIN mutants, confirming that they share a common role in mitochondrial biology (Burchell et al 2013 ; Zhou et al 2016 ). As a result, it is assumed that FBXO7 functions in a common pathway with PARKIN and PINK1 to induce selective autophagic clearance (mitophagy) in response to damaged mitochondria and pathogenic mutations in FBXO7 may interfere with this pathway (Conedera et al 2016 ; Randle and Laman 2017 ; Vingill et al 2016 ).…”

Section: Pink1 Parkin and Mitochondrial Hemostasismentioning

confidence: 99%

Parkinson Disease from Mendelian Forms to Genetic Susceptibility: New Molecular Insights into the Neurodegeneration Process

et al. 2018

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Parkinson disease (PD) is known as a common progressive neurodegenerative disease which is clinically diagnosed by the manifestation of numerous motor and nonmotor symptoms. PD is a genetically heterogeneous disorder with both familial and sporadic forms. To date, researches in the field of Parkinsonism have identified 23 genes or loci linked to rare monogenic familial forms of PD with Mendelian inheritance. Biochemical studies revealed that the products of these genes usually play key roles in the proper protein and mitochondrial quality control processes, as well as synaptic transmission and vesicular recycling pathways within neurons. Despite this, large number of patients affected with PD typically tends to show sporadic forms of disease with lack of a clear family history. Recent genome-wide association studies (GWAS) meta-analyses on the large sporadic PD case–control samples from European populations have identified over 12 genetic risk factors. However, the genetic etiology that underlies pathogenesis of PD is also discussed, since it remains unidentified in 40% of all PD-affected cases. Nowadays, with the emergence of new genetic techniques, international PD genomics consortiums and public online resources such as PDGene, there are many hopes that future large-scale genetics projects provide further insights into the genetic etiology of PD and improve diagnostic accuracy and therapeutic clinical trial designs.

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Section: Pink1 Parkin and Mitochondrial Hemostasismentioning

confidence: 99%

Parkinson Disease from Mendelian Forms to Genetic Susceptibility: New Molecular Insights into the Neurodegeneration Process

et al. 2018

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“…In a similar vein to the sperm maturation defects, Fbxo7 has also been shown to be required during the final maturation steps of erythrocytes. We previously reported Fbxo7 LacZ/LacZ mice are anemic due to delayed mitophagy and defects in exiting cell cycle (Randle and Laman, 2016). Importantly, during this maturation step, macrophages in erythroblast islands phagocytose the shed organelles from maturing reticulocytes (Geminard et al, 2002; Zhang et al, 2015; Ovchynnikova et al, 2018), a process requiring the coupling of the autophagy and exocytosis pathways (Mankelow et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

A Conserved Requirement for Fbxo7 During Male Germ Cell Cytoplasmic Remodeling

et al. 2019

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Fbxo7 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 hematopoietic phenotypes, male mice with reduced Fbxo7 expression are 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 spermatids undergo cytoplasmic remodeling. 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 mutant males. Mutation of the Drosophila Fbxo7 ortholog, nutcracker (ntc) also leads to sterility with germ cell death during cytoplasmic remodeling, indicating that the requirement for Fbxo7 at this stage is conserved. The ntc phenotype was attributed to decreased levels of the proteasome regulator, DmPI31 and reduced proteasome activity. Consistent with the fly model, we observe a reduction in PI31 levels in mutant mice; however, there is no alteration in proteasome activity in whole mouse testes. Our results are consistent with findings that Fbxo7 regulates PI31 protein levels, and indicates that a defect at the late stages of spermiogenesis, possibly due to faulty spatial dynamics of proteasomes during cytoplasmic remodeling, may underlie the fertility phenotype in mice.

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“…This protein is likely essential for LANCL2 mediated downregulation of inflammatory pathways because of its previously explored abilities to mark important TNF and TRAF signaling molecules for degradation [52]. Notably, Fbxo7 and members of the LanC-like family have been shown to impact similar neurological disorders [53,54]. Moreover, LANCL2 is important for the production of secondary messengers such as cAMP and Ca 2+ , which help to drive PKA and calmodulin events needed for the elevated production of IL-10 [48].…”

Section: Discussionmentioning

confidence: 99%

Modeling the Role of Lanthionine Synthetase C-Like 2 (LANCL2) in the Modulation of Immune Responses to Helicobacter pylori Infection

et al. 2016

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Immune responses to Helicobacter pylori are orchestrated through complex balances of host-bacterial interactions, including inflammatory and regulatory immune responses across scales that can lead to the development of the gastric disease or the promotion of beneficial systemic effects. While inflammation in response to the bacterium has been reasonably characterized, the regulatory pathways that contribute to preventing inflammatory events during H. pylori infection are incompletely understood. To aid in this effort, we have generated a computational model incorporating recent developments in the understanding of H. pylori-host interactions. Sensitivity analysis of this model reveals that a regulatory macrophage population is critical in maintaining high H. pylori colonization without the generation of an inflammatory response. To address how this myeloid cell subset arises, we developed a second model describing an intracellular signaling network for the differentiation of macrophages. Modeling studies predicted that LANCL2 is a central regulator of inflammatory and effector pathways and its activation promotes regulatory responses characterized by IL-10 production while suppressing effector responses. The predicted impairment of regulatory macrophage differentiation by the loss of LANCL2 was simulated based on multiscale linkages between the tissue-level gastric mucosa and the intracellular models. The simulated deletion of LANCL2 resulted in a greater clearance of H. pylori, but also greater IFNγ responses and damage to the epithelium. The model predictions were validated within a mouse model of H. pylori colonization in wild-type (WT), LANCL2 whole body KO and myeloid-specific LANCL2-/- (LANCL2Myeloid) mice, which displayed similar decreases in H. pylori burden, CX3CR1+ IL-10-producing macrophages, and type 1 regulatory (Tr1) T cells. This study shows the importance of LANCL2 in the induction of regulatory responses in macrophages and T cells during H. pylori infection.

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Structure and Function of Fbxo7/PARK15 in Parkinson's Disease

Cited by 22 publications

References 77 publications

Parkinson Disease from Mendelian Forms to Genetic Susceptibility: New Molecular Insights into the Neurodegeneration Process

Parkinson Disease from Mendelian Forms to Genetic Susceptibility: New Molecular Insights into the Neurodegeneration Process

A Conserved Requirement for Fbxo7 During Male Germ Cell Cytoplasmic Remodeling

Modeling the Role of Lanthionine Synthetase C-Like 2 (LANCL2) in the Modulation of Immune Responses to Helicobacter pylori Infection

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