Vps35 in cooperation with LRRK2 regulates synaptic vesicle endocytosis through the endosomal pathway in Drosophila

Inoshita, Tsuyoshi; Arano, Taku; Hosaka, Yuka; Meng, Hui; Umezaki, Yujiro; Kosugi, Sakiko; Morimoto, Takako; Koike, Masato; Chang, Hui-Yun; Imai, Yuzuru; Hattori, Nobutaka

doi:10.1093/hmg/ddx179

Cited by 110 publications

(129 citation statements)

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“…In addition, variation in genes that encode core components of the autophagic machinery, the proteins Atg5 and Atg7, is reported risk factors for PD (Chen et al, 2013a, 2013b). Lastly, recent work also found that variation in the EndoA1 gene constitutes a risk factor for PD (Chang et al, 2017). We and others showed that EndoA plays a prominent role in synaptic autophagy in fruit flies and mice (Murdoch et al, 2016;Soukup et al, 2016).…”

Section: Macroautophagy and Mitophagymentioning

confidence: 53%

“…EndoA is emerging as a central nexus of synaptic biology in the context of PD. Not only is EndoA phosphorylated by LRRK2, but the protein also binds to Parkin and Synj1 (Schuske et al, 2003;Verstreken et al, 2003;Trempe et al, 2009;Cao et al, 2014;Fig 2) and variation at the EndoA1 locus (SH3GL2) is a risk factor for PD (Chang et al, 2017). Mutations in either parkin or SYNJ1 cause an autosomal-recessive early-onset form of PD, and mutations in Synj1 are in general more severe (Krebs et al, 2013;Quadri et al, 2013;Olgiati et al, 2014;Kirola et al, 2016).…”

Section: Endoamentioning

confidence: 99%

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Parkinson's disease: convergence on synaptic homeostasis

2018

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Parkinson's disease, the second most common neurodegenerative disorder, affects millions of people globally. There is no cure, and its prevalence will double by 2030. In recent years, numerous causative genes and risk factors for Parkinson's disease have been identified and more than half appear to function at the synapse. Subtle synaptic defects are thought to precede blunt neuronal death, but the mechanisms that are dysfunctional at synapses are only now being unraveled. Here, we review recent work and propose a model where different Parkinson proteins interact in a cell compartment-specific manner at the synapse where these proteins regulate endocytosis and autophagy. While this field is only recently emerging, the work suggests that the loss of synaptic homeostasis may contribute to neurodegeneration and is a key player in Parkinson's disease.

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Section: Macroautophagy and Mitophagymentioning

confidence: 53%

Section: Endoamentioning

confidence: 99%

Parkinson's disease: convergence on synaptic homeostasis

2018

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“…To explore the requirement of retromer at synapses, we next turned to the larval neuromuscular junction (NMJ). Based on previous work, Vps35 is present at both the NMJ pre-and post-synapse, and loss of Vps35 causes synaptic terminal overgrowth and altered neurophysiology suggestive of synaptic vesicle recycling defects (Inoshita et al, 2017;Korolchuk et al, 2007;Malik et al, 2015;Walsh et al, 2019). We therefore examined whether Vps29 mutants show similar phenotypes.…”

Section: Retromer Regulates Synaptic Vesicle Endocytosis and Recyclingmentioning

confidence: 99%

“…Originally discovered in the yeast S. cerevisiae (Seaman et al, 1998), the heterotrimeric core proteins of the retromer, VPS35, VPS26, and VPS29, are highly conserved among eukaryotes (Koumandou et al, 2011). Retromer components are broadly expressed, including in the invertebrate nervous system (Inoshita et al, 2017;Wang et al, 2014) and throughout the mammalian brain (Appel et al, 2018;Tsika et al, 2014). In murine neurons, retromer is present in both axons and dendrites, and at the synapse (Munsie et al, 2015;Tsika et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Post-synaptically, retromer appears important for trafficking of AMPA, β2 adrenergic, and perhaps other neurotransmitter receptors to the dendritic membrane (Choy et al, 2014;Munsie et al, 2015;Temkin et al, 2017). In rat mesencephalic cultures, retromer also participates in pre-synaptic dopamine transporter trafficking (Wu et al, 2017), and studies of Vps35 at the Drosophila neuromuscular junction are suggestive of a requirement for synaptic vesicle recycling (Inoshita et al, 2017). Vps35-deficient mice exhibit both defective hippocampal neurotransmission (Muhammad et al, 2008) and dopaminergic insufficiency (Tang et al, 2015a(Tang et al, , 2015b, leading to impairments in memory and locomotion, respectively.…”

Section: Introductionmentioning

confidence: 99%

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Retromer subunit, VPS29, regulates synaptic transmission and is required for endolysosomal function in the aging brain

Ojelade

Li‐Kroeger

et al. 2019

Preprint

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AbstractRetromer, including Vps35, Vps26, and Vps29, is a protein complex responsible for recycling proteins within the endolysosomal pathway. Although implicated in both Parkinson’s and Alzheimer’s disease, our understanding of retromer function in the adult brain remains limited, in part because Vps35 and Vps26 are essential for development. In Drosophila, we find that Vps29 is dispensable for embryogenesis but required for retromer function in aging adults, including for synaptic transmission, survival, and locomotion. Unexpectedly, in Vps29 mutants, Vps35 and Vps26 proteins are normally expressed and associated, but retromer is mislocalized from neuropil to soma with the Rab7 GTPase. Further, Vps29 phenotypes are suppressed by reducing Rab7 or overexpressing the GTPase activating protein, TBC1D5. With aging, retromer insufficiency triggers progressive endolysosomal dysfunction, with ultrastructural evidence of impaired substrate clearance and lysosomal stress. Our results reveal the role of Vps29 in retromer localization and function, highlighting requirements for brain homeostasis in aging.Impact StatementVps29 promotes retromer localization in the adult Drosophila brain, engaging Rab7 and TBC1D5, and its loss triggers age-dependent neuronal impairments in endolysosomal trafficking and synaptic transmission.

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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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Vps35 in cooperation with LRRK2 regulates synaptic vesicle endocytosis through the endosomal pathway in Drosophila

Cited by 110 publications

References 52 publications

Parkinson's disease: convergence on synaptic homeostasis

Parkinson's disease: convergence on synaptic homeostasis

Retromer subunit, VPS29, regulates synaptic transmission and is required for endolysosomal function in the aging brain

The functional roles of retromer in Parkinson's disease

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