Parkinson’s Disease Genes VPS35 and EIF4G1 Interact Genetically and Converge on α-Synuclein

Dhungel, Nripesh; Eleuteri, Simona; Li, Ling Bo; Kramer, Nicholas J.; Chartron, J.W.; Spencer, Brian; Kosberg, Kori; Fields, Jerel Adam; Stafa, Klodjan; Adame, Anthony; Lashuel, Hilal A.; Frydman, Judith; Shen, Kang; Masliah, Eliezer; Gitler, Aaron D.

doi:10.1016/j.neuron.2015.01.022

Cited by 14 publications

(23 citation statements)

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“…Consistent with the above observations, Vps35 loss-of-function enhances a-synuclein toxicity in yeast and C. elegans [108]. In contrast, overexpressing of wild-type Vps35 in a-synuclein transgenic mouse models almost completely rescues the neurodegeneration induced by a-synuclein [108]. However, the presence of PD-linked variant Vps35 D620N or Vps35 P316S, or knock down of endogenous Vps35 causes more neuronal loss in the hippocampus from a-synuclein transgenic mouse, suggesting the functional role of retromer in antagonizing a-synuclein-associated neurodegeneration [108].…”

Section: Connectivity Of Retromer With Other Pdassociated Proteinssupporting

confidence: 86%

“…Hence, it is likely that retromer functional deficiency contributes to a-synuclein aggregation in an indirect manner, thereby further leading to PD progression. Consistent with the above observations, Vps35 loss-of-function enhances a-synuclein toxicity in yeast and C. elegans [108]. In contrast, overexpressing of wild-type Vps35 in a-synuclein transgenic mouse models almost completely rescues the neurodegeneration induced by a-synuclein [108].…”

Section: Connectivity Of Retromer With Other Pdassociated Proteinssupporting

confidence: 83%

“…In contrast, overexpressing of wild-type Vps35 in a-synuclein transgenic mouse models almost completely rescues the neurodegeneration induced by a-synuclein [108]. However, the presence of PD-linked variant Vps35 D620N or Vps35 P316S, or knock down of endogenous Vps35 causes more neuronal loss in the hippocampus from a-synuclein transgenic mouse, suggesting the functional role of retromer in antagonizing a-synuclein-associated neurodegeneration [108]. The connection between retromer and a-synuclein is further supported by evidence from recent proteomic studies [109].…”

Section: Connectivity Of Retromer With Other Pdassociated Proteinsmentioning

confidence: 92%

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The functional roles of retromer in Parkinson's disease

2017

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The endosomal system is critical for the maintenance of intracellular homeostasis, and defects in this system are often linked to neurological disorders. The retromer complex is a critical coordinator of endosomal dynamics and has functional roles in multiple cellular processes through sorting cargoes from endosomes to the trans-Golgi network (TGN) or to the plasma membrane. Mammalian retromer comprises a core Vps26-Vps35-Vps29 trimer and associates with a range of proteins to generate endosomal tubular-vesicular carriers. Alterations in retromer function or its molecular organization have been a rising risk factor for Parkinson's disease (PD). Although genetic evidence has shown several variants within retromer in late-onset PD cases, the exact molecular machineries by which retromer variants induce the development of PD are still not completely elucidated. In this Review, we will focus on the functional roles of retromer in neuronal health, summarize advances in defining the cellular pathological phenotype caused by retromer deficiency or PD-linked retromer variants and discuss the potential clues of how retromer deregulation may contribute to PD pathogenesis.Keywords: autophagy; endosomal trafficking; lysosome; mitochondria; Parkinson's disease (PD); retromer The endosomal network is a highly dynamic and orchestrated system, which serves a vital function in coordinating the communication and exchange of associated proteins and lipids between intracellular membrane-bounded compartments. Once within the network, cargo molecules originating from the plasma membrane and biosynthetic pathways are targeted to a common sorting station, the early endosome, from where cargoes are sorted towards specialized intracellular locations following multiple trafficking routes. They can be either sorted into late endosomes/ lysosomes for degradation or retrieved to the plasma membrane or the trans-Golgi network (TGN). The efficient and accurate delivery of cargo contents within intracellular compartments is critical for the maintenance of intracellular homeostasis, and defects on it are often associated with multiple human diseases. The evolutionary conserved protein complex, termed Abbreviations AMPAR, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; APEX, ascorbate peroxidase; APP, b-amyloid precursor protein; ATG9A, autophagy-associated protein; Ab, elevated b-amyloid peptide; BAR, Bin-Amphiphysin-Rvs; BDNF, brain-derived neurotrophic factor; CI-M6PR, cation-independent mannose 6-phosphate receptor; CLN5, ceroid lipouscinosis neuronal protein-5; CMA, chaperon-mediated autophagy; Crb, crumb; DA, dopaminergic; DMTI-II, divalent metal transporter II; DRD1, dopamine receptor D1; Drp1, dynamin-related protein 1; EHD1, Eps15 homology domain-containing protein-1; FERM, 4.1/ezrin/radixin/moesin; GLUT1, glucose transporter 1; Kir3, G protein-gated inward rectifying potassium channels; Lamp2a, lysosome-associated membrane glycoprotein 2a; LBs, Lewy bodies; MAPL, mitochondria-anchored protein ligase; MDVs, mitochondria-de...

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Section: Connectivity Of Retromer With Other Pdassociated Proteinssupporting

confidence: 86%

Section: Connectivity Of Retromer With Other Pdassociated Proteinssupporting

confidence: 83%

Section: Connectivity Of Retromer With Other Pdassociated Proteinsmentioning

confidence: 92%

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The functional roles of retromer in Parkinson's disease

2017

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“…Testing of the functional effects of these pathogenic variants on protein translation has begun, and the eIF4G1 p.R1205H mutation might deregulate protein translation (Chartier-Harlin, unpublished data and [18]). More recently, eIF4G1 was found to interact genetically in yeast with another PD gene, the vacuolar protein sortingassociated protein 35 (VPS35), indicating that protein deregulation pathways of eIF4G1 involves other genetic factors of PD [19]. Further links between PD and translation come from studies investigating the leucine-rich repeat kinase 2 (LRRK2) signaling pathway.…”

Section: Genetic Links Between Pd and Protein Translationmentioning

confidence: 99%

Deregulation of protein translation control, a potential game-changing hypothesis for Parkinson's disease pathogenesis

Taymans

Nkiliza

Chartier-Harlin

2015

Trends in Molecular Medicine

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“…More generally, it was recently hypothesized that deregulation of translation control might be a crucial factor in PD pathogenesis, which might have so far been overlooked [67]. The translation initiation factor eIF4G1 might be in the PD pathway [68,69] possibly also through its ability to reprogram translation under stress conditions [70].…”

Section: Mitochondrial Dysfunction and Its Link To Pdmentioning

confidence: 99%

Dissecting the role of Engrailed in adult dopaminergic neurons – Insights into Parkinson disease pathogenesis

et al. 2015

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Edited by Wilhelm JustKeywords: Dopaminergic neuron Homeoprotein Parkinson disease Engrailed Mitochondria Substantia nigra pars compacta Retrograde degeneration a b s t r a c tThe homeoprotein Engrailed (Engrailed-1/Engrailed-2, collectively En1/2) is not only a survival factor for mesencephalic dopaminergic (mDA) neurons during development, but continues to exert neuroprotective and physiological functions in adult mDA neurons. Loss of one En1 allele in the mouse leads to progressive demise of mDA neurons in the ventral midbrain starting from 6 weeks of age. These mice also develop Parkinson disease-like motor and non-motor symptoms. The characterization of En1 heterozygous mice have revealed striking parallels to central mechanisms of Parkinson disease pathogenesis, mainly related to mitochondrial dysfunction and retrograde degeneration. Thanks to the ability of homeoproteins to transduce cells, En1/2 proteins have also been used to protect mDA neurons in various experimental models of Parkinson disease. This neuroprotection is partly linked to the ability of En1/2 to regulate the translation of certain nuclear-encoded mitochondrial mRNAs for complex I subunits. Other transcription factors that govern mDA neuron development (e.g. Foxa1/2, Lmx1a/b, Nurr1, Otx2, Pitx3) also continue to function for the survival and maintenance of mDA neurons in the adult and act through partially overlapping but also diverse mechanisms.

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Parkinson’s Disease Genes VPS35 and EIF4G1 Interact Genetically and Converge on α-Synuclein

Cited by 14 publications

References 0 publications

The functional roles of retromer in Parkinson's disease

The functional roles of retromer in Parkinson's disease

Deregulation of protein translation control, a potential game-changing hypothesis for Parkinson's disease pathogenesis

Dissecting the role of Engrailed in adult dopaminergic neurons – Insights into Parkinson disease pathogenesis

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