Parkin-Dependent Degradation of the F-Box Protein Fbw7β Promotes Neuronal Survival in Response to Oxidative Stress by Stabilizing Mcl-1

Ekholm-Reed, Susanna; Goldberg, Matthew S.; Schlossmacher, Michael G.; Reed, Steven I.

doi:10.1128/mcb.00535-13

Cited by 68 publications

(61 citation statements)

References 104 publications

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“…Also recovered in the spatial map was PARKIN (PARK2) . While PARKIN does not have a direct yeast homolog, a related ubiquitin ligase in yeast, Cdc4 (FBXW7)(Ivatt et al 2014; Ekholm-Reed et al 2013), was recovered in our genetic screens. A third PARK gene, DNAJC6 (PARK19) (Köroğlu et al 2013; Olgiati et al 2015; Edvardson et al 2012), was recovered in the spatial map.…”

Section: Resultsmentioning

confidence: 96%

In Situ Peroxidase Labeling and Mass-Spectrometry Connects Alpha-Synuclein Directly to Endocytic Trafficking and mRNA Metabolism in Neurons

et al. 2017

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Synucleinopathies, including Parkinson’s disease (PD), are associated with the misfolding and mistrafficking of alpha-synuclein (α-syn). Here, using an ascorbate peroxidase (APEX)-based labeling method combined with mass spectrometry, we defined a network of proteins in the immediate vicinity of α-syn in living neurons to shed light on α-syn function. This approach identified 225 proteins, including synaptic proteins, proteins involved in endocytic vesicle trafficking, the retromer complex, phosphatases and mRNA binding proteins. Many were in complexes with α-syn, and some were encoded by genes known to be risk factors for PD and other neurodegenerative diseases. Endocytic trafficking and mRNA translation proteins within this spatial α-syn map overlapped with genetic modifiers of α-syn toxicity, developed in an accompanying study (Khurana et al, 2016). Our data suggest that perturbation of these particular pathways is directly related to the spatial localization of α-syn within the cell. These approaches provide new avenues to systematically examine protein function and pathology in living cells.

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Section: Resultsmentioning

confidence: 96%

In Situ Peroxidase Labeling and Mass-Spectrometry Connects Alpha-Synuclein Directly to Endocytic Trafficking and mRNA Metabolism in Neurons

et al. 2017

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“…On the other hand, it may be that the relevant function of FBXW7 is SREBPindependent. FBXW7 is expressed as three isoforms, with FBXW7α and FBXW7γ regulating cyclin E degradation in the nucleus (27), whereas cytoplasmic FBXW7β promotes the degradation of the mitochondrial prosurvival factor Mcl-1 (21). In response to oxidative stress, Parkin targets the proteasomal degradation of FBXW7β to allow Mcl-1 stabilization and promote neuron survival.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, SREBF1 has been reported as a risk locus in GWASs for sporadic PD (10). In addition, FBXW7 has been shown to function directly with Parkin, promoting neuronal survival by regulating the levels of cyclin E and the mitochondrial prosurvival factor Mcl-1 (21,22). Therefore, follow-up analysis assessed the relationship between PINK1, Parkin, and components of the SREBP lipogenesis pathway.…”

Section: Rnai Screening Identified 20 Genes With a Conserved Role In mentioning

confidence: 99%

Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locusSREBF1as a regulator of mitophagy

Ivatt

Sánchez-Martínez

Godena

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

117

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Genetic analysis of Parkinson disease (PD) has identified several genes whose mutation causes inherited parkinsonism, as well as risk loci for sporadic PD. PTEN-induced kinase 1 (PINK1) and parkin, linked to autosomal recessive PD, act in a common genetic pathway regulating the autophagic degradation of mitochondria, termed mitophagy. We undertook a genome-wide RNAi screen as an unbiased approach to identify genes regulating the PINK1/Parkin pathway. We identified several genes that have a conserved function in promoting mitochondrial translocation of Parkin and subsequent mitophagy, most notably sterol regulatory element binding transcription factor 1 (SREBF1), Fbox and WD40 domain protein 7 (FBXW7), and other components of the lipogenesis pathway. The relevance of mechanisms of autosomal recessive parkinsonism to sporadic PD has long been debated. However, with the recent identification of SREBF1 as a risk locus for sporadic PD, our findings suggest a common mechanistic link between autosomal recessive and sporadic PD, and underscore the importance of mitochondrial homeostasis. P arkinson disease (PD) is an age-related neurodegenerative disease caused principally by the loss of midbrain dopaminergic neurons, resulting in motor disturbances, such as postural instability, resting tremor, and bradykinesia, as well as other nonmotor symptoms. Current therapeutic strategies alleviate symptoms by the replacement of dopamine, with variable efficacy and substantial side effects. However, there are currently no established curative, preventative, or disease-modifying interventions, stemming from a poor understanding of the molecular mechanisms of pathogenesis. Genetic analyses have identified causative mutations for autosomal dominant and recessive forms of familial parkinsonism. Functional studies of these genes have provided great insight into potential pathogenic mechanisms of inherited forms of PD; however, it is unclear how these may relate to the more common sporadic forms of PD. To gain insight into the genetic influence in sporadic PD, genome-wide association studies (GWASs) have revealed several loci that are significantly associated with the occurrence of PD, and so are considered potential risk factors. However, we lack mechanistic insight into how many of the associated risk loci may contribute to pathogenesis.Mitochondrial dysfunction has long been considered a key contributing factor in the pathogenesis of PD, with evidence from postmortem tissue, epidemiological studies, and genetics. In particular, a body of evidence indicates that two genes linked to recessive parkinsonism, PTEN-induced kinase 1 (PINK1) and parkin, act in a common pathway to regulate mitochondrial turnover, providing an attractive hypothesis for the impact of mitochondrial homeostasis on pathogenesis (1). The process of mitophagy to degrade dysfunctional mitochondria has been extensively studied using uncoupling agents to dissipate the mitochondrial membrane potential (ΔΨm) (2). Following loss of ΔΨm, PINK1 accumulates on the outer mit...

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“…1B) (Hao et al, 2007; Orlicky et al, 2003; Tang et al, 2007; Welcker and Clurman, 2007; Welcker et al, 2013; Zhang and Koepp, 2006). Fbw7α is thought to perform most Fbw7 functions, although specific roles for the other isoforms have also been described (Bonetti et al, 2008; Ekholm-Reed et al, 2013; Grim et al, 2008; Matsumoto et al, 2011; van Drogen et al, 2006; Welcker et al, 2004a). …”

Section: Fbw7 Is a Ubiquitin Ligase Substrate Receptormentioning

confidence: 99%

“…One example is Fbw7β degradation by Parkin, which subsequently inhibits MCL-1 degradation (Ekholm-Reed et al, 2013). It has also been suggested that Pin1 overexpression in cancers destabilizes Fbw7 by directly generating Fbw7 monomers that are targeted for degradation through enhanced autoubiquitylation (Min et al, 2012).…”

Section: Additional Mechanisms Of Fbw7 Disruption In Cancermentioning

confidence: 99%

Tumor Suppression by the Fbw7 Ubiquitin Ligase: Mechanisms and Opportunities

2014

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Summary Tumor suppressors with widespread impact on carcinogenesis control broad spectra of oncogenic pathways. Protein degradation is an emerging mechanism by which tumor suppressors regulate a diversity of pathways and is exemplified by the SCFFbw7 ubiquitin ligase. Rapidly accumulating data indicate that SCFFbw7 regulates a network of crucial oncoproteins. Importantly, the FBXW7 gene, which encodes Fbw7, is one of the most frequently mutated genes in human cancers. These studies are yielding important new insights into tumorigenesis and may soon enable therapies targeting the Fbw7 pathway. Here, we focus on the mechanisms and consequences of Fbw7 deregulation in cancers and discuss possible therapeutic approaches.

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Parkin-Dependent Degradation of the F-Box Protein Fbw7β Promotes Neuronal Survival in Response to Oxidative Stress by Stabilizing Mcl-1

Cited by 68 publications

References 104 publications

In Situ Peroxidase Labeling and Mass-Spectrometry Connects Alpha-Synuclein Directly to Endocytic Trafficking and mRNA Metabolism in Neurons

In Situ Peroxidase Labeling and Mass-Spectrometry Connects Alpha-Synuclein Directly to Endocytic Trafficking and mRNA Metabolism in Neurons

Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locusSREBF1as a regulator of mitophagy

Tumor Suppression by the Fbw7 Ubiquitin Ligase: Mechanisms and Opportunities

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