Parkinson Disease-linked Vps35 R524W Mutation Impairs the Endosomal Association of Retromer and Induces α-Synuclein Aggregation

Follett, Jordan; Bugarčić, Andrea; Yang, Zhe; Ariotti, Nicholas; Norwood, Suzanne J.; Collins, Brett M.; Parton, Robert G.; Teasdale, Rohan D.

doi:10.1074/jbc.m115.703157

Cited by 78 publications

(67 citation statements)

References 54 publications

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“…This is supported by observations made in Vps35-knockdown Drosophila models, demonstrating that loss of retromer Vps35 subunit not only induces the accumulation of insoluble a-synuclein in brain but also causes locomotor impairments and the mild compound eye disorganization [84]. Similar defects on cathepsin D processing and asynuclein degradation are observed in cellular models overexpressing the Vps35 D620N or Vps35 R524W variants [86,87]. Hence, it is likely that retromer functional deficiency contributes to a-synuclein aggregation in an indirect manner, thereby further leading to PD progression.…”

Section: Connectivity Of Retromer With Other Pdassociated Proteinssupporting

confidence: 72%

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: 72%

The functional roles of retromer in Parkinson's disease

2017

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“…Insofar, all genetic mutations identified in SNX27 or retromer in humans have been linked to severe neuropathologies including Alzheimer’s disease [83], Parkinson’s disease [84, 85], Down syndrome [86] and infantile epilepsy [87] for recent reviews see [88, 89]. Accordingly, lowered expression of SNX27 or retromer reduces the surface cell levels of several cargo known to influence synaptic neurotransmission (N-methyl-D-aspartate receptors; NMDARs [90] and AMPARs[91], neuronal signaling and excitably (β 2 AR [90], GIRK2a [92] mGLuR5 [93]), glial cell differentiation (GPCR 17; GPR17 [94]) and, more recently, limiting the distribution of amyloid precursor protein (APP), a precursor linked to the onset and progression of Alzheimer’s disease [95].…”

Section: Figurementioning

confidence: 99%

GPCR Signaling and Trafficking: The Long and Short of It

Pavlos

Friedman

2017

Trends in Endocrinology & Metabolism

167

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Emerging findings disclose unexpected components of G protein-coupled receptor (GPCR) signaling and cell biology. Select GPCRs exhibit classical signaling that is restricted to cell membranes and newly described persistent signaling that depends on internalization of the GPCR bound to β-arrestins. Termination of non-canonical endosomal signaling requires intraluminal acidification and sophisticated protein trafficking machineries. Recent studies reveal the structural determinants of the trafficking chaperones. This review summarizes advances in GPCR signaling and trafficking with a focus on the parathyroid hormone receptor as prototype, and the actin-SNX27-retromer tubule complex, an endosomal sorting hub responsible for recycling and preservation of cell surface receptors. The findings are integrated into a model of PTHR trafficking with implications for signal transduction, bone growth, and mineral-ion metabolism.

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“…In humans and yeast, altered retromer function is associated with impaired trafficking of lysosomal/vacuolar enzymes that results in their secretion into the extracellular space (Bonangelino et al, 2002;Follett et al, 2016;Rojas et al, 2008). We asked if Rab7 palmitoylation is required for the correct trafficking of the lysosomal enzyme cathepsin D. To test the effect of Rab7 palmitoylation on cathepsin D trafficking, we compared the secretion of cathepsin D in HEK-293 cells, Rab7-KO cells and Rab7-KO cells transiently expressing wild-type Myc-Rab7 and the various mutants (Fig.…”

Section: Palmitoylation Modulates the Interaction Between Rab7 And Rementioning

confidence: 99%

“…A cathepsin D secretion assay was performed as previously described (Follett et al, 2016). Briefly, HEK-293 and Rab7-KO cells were transfected with the indicated plasmids.…”

Section: Cathepsin D Secretion Assaymentioning

confidence: 99%

Rab7 palmitoylation is required for efficient endosome-to-TGN trafficking

Modica

Skorobogata

Sauvageau

et al. 2017

Journal of Cell Science

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Retromer is a multimeric protein complex that mediates endosometo-trans-Golgi network (TGN) and endosome-to-plasma membrane trafficking of integral membrane proteins. Dysfunction of this complex has been linked to Alzheimer's disease and Parkinson's disease. The recruitment of retromer to endosomes is regulated by Rab7 (also known as RAB7A) to coordinate endosome-to-TGN trafficking of cargo receptor complexes. Rab7 is also required for the degradation of internalized integral membrane proteins, such as the epidermal growth factor receptor (EGFR). We found that Rab7 is palmitoylated and that this modification is not required for membrane anchoring. Palmitoylated Rab7 colocalizes efficiently with and has a higher propensity to interact with retromer than nonpalmitoylatable Rab7. Rescue of Rab7 knockout cells by expressing wild-type Rab7 restores efficient endosome-to-TGN trafficking, while rescue with nonpalmitoylatable Rab7 does not. Interestingly, Rab7 palmitoylation does not appear to be required for the degradation of EGFR or for its interaction with its effector, Rab-interacting lysosomal protein (RILP). Overall, our results indicate that Rab7 palmitoylation is required for the spatiotemporal recruitment of retromer and efficient endosome-to-TGN trafficking of the lysosomal sorting receptors.

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Parkinson Disease-linked Vps35 R524W Mutation Impairs the Endosomal Association of Retromer and Induces α-Synuclein Aggregation

Cited by 78 publications

References 54 publications

The functional roles of retromer in Parkinson's disease

The functional roles of retromer in Parkinson's disease

GPCR Signaling and Trafficking: The Long and Short of It

Rab7 palmitoylation is required for efficient endosome-to-TGN trafficking

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