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- 검색키워드
- 저자 : Minyeop Nahm (검색결과 9 건)
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MICAL-like Regulates Fasciclin II Membrane Cycling and Synaptic Development
Nahm, Minyeop,Park, Sunyoung,Lee, Jihye,Lee, Seungbok Korean Society for Molecular and Cellular Biology 2016 Molecules and cells Vol.39 No.10
Fasciclin II (FasII), the Drosophila ortholog of neural cell adhesion molecule (NCAM), plays a critical role in synaptic stabilization and plasticity. Although this molecule undergoes constitutive cycling at the synaptic membrane, how its membrane trafficking is regulated to ensure proper synaptic development remains poorly understood. In a genetic screen, we recovered a mutation in Drosophila mical-like that displays an increase in bouton numbers and a decrease in FasII levels at the neuromuscular junction (NMJ). Similar phenotypes were induced by presynaptic, but not postsynaptic, knockdown of mical-like expression. FasII trafficking assays revealed that the recycling of internalized FasII molecules to the cell surface was significantly impaired in mical-like-knockdown cells. Importantly, this defect correlated with an enhancement of endosomal sorting of FasII to the lysosomal degradation pathway. Similarly, synaptic vesicle exocytosis was also impaired in mical-like mutants. Together, our results identify Mical-like as a novel regulator of synaptic growth and FasII endocytic recycling.
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Nahm, Minyeop,Kim, Sungdae,Paik, Sang Kyoo,Lee, Mihye,Lee, Seongsoo,Lee, Zang Hee,Kim, Jaesang,Lee, Daekee,Bae, Yong Chul,Lee, Seungbok The Society 2010 The Journal of neuroscience Vol.30 No.24
<P>The bone morphogenetic protein (BMP) ligand Glass bottom boat (Gbb) acts as a retrograde growth signal at the Drosophila neuromuscular junction (NMJ). Endocytic regulation of presynaptic BMP receptors has been proposed to attenuate retrograde BMP signaling. However, it remains unknown whether the Gbb signal is also regulated by postsynaptic mechanisms. Here, we provide evidence that Drosophila Cdc42-interacting protein 4 (dCIP4) functions postsynaptically to inhibit synaptic growth. dCIP4 is localized postsynaptically at NMJs. dcip4 mutations lead to synaptic overgrowth and increased presynaptic phosphorylated mothers against decapentaplegic (Mad) levels, and these defects are rescued by muscle-specific expression of dCIP4. Biochemical and genetic analyses demonstrate that dCIP4 acts downstream of Cdc42 to activate the postsynaptic Wsp-Arp2/3 pathway. We also show that BMP signaling is necessary for synaptic overgrowth in larvae lacking postsynaptic dcip4 or wsp. Finally, dCIP4 and Wsp inhibit Gbb secretion. Thus, we propose that dCIP4 restrains synaptic growth by inhibiting postsynaptic Gbb secretion through the Wsp-Arp2/3 pathway.</P>
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Nahm, Minyeop,Long, A. Ashleigh,Paik, Sang Kyoo,Kim, Sungdae,Bae, Yong Chul,Broadie, Kendal,Lee, Seungbok The Rockefeller University Press 2010 The Journal of cell biology Vol.191 No.3
<P>Retrograde bone morphogenetic protein signaling mediated by the Glass bottom boat (Gbb) ligand modulates structural and functional synaptogenesis at the <I>Drosophila melanogaster</I> neuromuscular junction. However, the molecular mechanisms regulating postsynaptic Gbb release are poorly understood. In this study, we show that <I>Drosophila</I> Rich (dRich), a conserved Cdc42-selective guanosine triphosphatase–activating protein (GAP), inhibits the Cdc42–Wsp pathway to stimulate postsynaptic Gbb release. Loss of dRich causes synaptic undergrowth and strongly impairs neurotransmitter release. These presynaptic defects are rescued by targeted postsynaptic expression of wild-type dRich but not a GAP-deficient mutant. dRich inhibits the postsynaptic localization of the Cdc42 effector Wsp (<I>Drosophila</I> orthologue of mammalian Wiskott-Aldrich syndrome protein, WASp), and manifestation of synaptogenesis defects in <I>drich</I> mutants requires Wsp signaling. In addition, dRich regulates postsynaptic organization independently of Cdc42. Importantly, dRich increases Gbb release and elevates presynaptic phosphorylated Mad levels. We propose that dRich coordinates the Gbb-dependent modulation of synaptic growth and function with postsynaptic development.</P>
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Graf regulates hematopoiesis through GEEC endocytosis of EGFR
Kim, Sungdae,Nahm, Minyeop,Kim, Najin,Kwon, Yumi,Kim, Joohyung,Choi, Sukwoo,Choi, Eun Young,Shim, Jiwon,Lee, Cheolju,Lee, Seungbok The Company of Biologists Limited 2017 Development Vol.144 No.22
<P>GTPase regulator associated with focal adhesion kinase 1 (GRAF1) is an essential component of the GPI-enriched endocytic compartment (GEEC) endocytosis pathway. Mutations in the human GRAF1 gene are associated with acute myeloid leukemia, but its normal role in myeloid cell development remains unclear. We show that Graf, the Drosophila ortholog of GRAF1, is expressed and specifically localizes to GEEC endocytic membranes in macrophage-like plasmatocytes. We also find that loss of Graf impairs GEEC endocytosis, enhances EGFR signaling and induces a plasmatocyte overproliferation phenotype that requires the EGFR signaling cascade. Mechanistically, Graf-dependent GEEC endocytosis serves as a major route for EGFR internalization at high, but not low, doses of the predominant Drosophila EGFR ligand Spitz (Spi), and is indispensable for efficient EGFR degradation and signal attenuation. Finally, Graf interacts directly with EGFR in a receptor ubiquitylation-dependent manner, suggesting a mechanism by which Graf promotes GEEC endocytosis of EGFR at high Spi. Based on our findings, we propose a model in which Graf functions to downregulate EGFR signaling by facilitating Spi-induced receptor internalization through GEEC endocytosis, thereby restraining plasmatocyte proliferation.</P>
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MICAL-like Regulates Fasciclin II Membrane Cycling and Synaptic Development
Seungbok Lee,Minyeop Nahm,Sunyoung Park,이지혜 한국분자세포생물학회 2016 Molecules and cells Vol.39 No.10
Fasciclin II (FasII), the Drosophila ortholog of neural cell adhesion molecule (NCAM), plays a critical role in synaptic stabilization and plasticity. Although this molecule undergoes constitutive cycling at the synaptic membrane, how its membrane trafficking is regulated to ensure proper synaptic development remains poorly understood. In a genetic screen, we recovered a mutation in Drosophila mical-like that displays an increase in bouton numbers and a decrease in FasII levels at the neuromuscular junction (NMJ). Similar phenotypes were induced by presynaptic, but not postsynaptic, knockdown of mical-like expression. FasII trafficking assays revealed that the recycling of internalized FasII molecules to the cell surface was significantly impaired in mical-like-knockdown cells. Importantly, this defect correlated with an enhancement of endosomal sorting of FasII to the lysosomal degradation pathway. Similarly, synaptic vesicle exocytosis was also impaired in mical-like mutants. Together, our results identify Mical-like as a novel regulator of synaptic growth and FasII endocytic recycling.
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Proteostasis and Ribostasis Impairment as Common Cell Death Mechanisms in Neurodegenerative Diseases
Su Min Lim,Minyeop Nahm,Seung Hyun Kim 대한신경과학회 2023 Journal of Clinical Neurology Vol.19 No.2
The cellular homeostasis of proteins (proteostasis) and RNA metabolism (ribostasis) are essential for maintaining both the structure and function of the brain. However, aging, cellular stress conditions, and genetic contributions cause disturbances in proteostasis and ribostasis that lead to protein misfolding, insoluble aggregate deposition, and abnormal ribonucleoprotein granule dynamics. In addition to neurons being primarily postmitotic, nondividing cells, they are more susceptible to the persistent accumulation of abnormal aggregates. Indeed, defects associated with the failure to maintain proteostasis and ribostasis are common pathogenic components of age-related neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Furthermore, the neuronal deposition of misfolded and aggregated proteins can cause both increased toxicity and impaired physiological function, which lead to neuronal dysfunction and cell death. There is recent evidence that irreversible liquid–liquid phase separation (LLPS) is responsible for the pathogenic aggregate formation of disease-related proteins, including tau, α-synuclein, and RNA-binding proteins, including transactive response DNA-binding protein 43, fused in sarcoma, and heterogeneous nuclear ribonucleoprotein A1. Investigations of LLPS and its control therefore suggest that chaperone/disaggregase, which reverse protein aggregation, are valuable therapeutic targets for effective treatments for neurological diseases. Here we review and discuss recent studies to highlight the importance of understanding the common cell death mechanisms of proteostasis and ribostasis in neurodegenerative diseases.
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Lee, Mihye,Paik, Sang Kyoo,Lee, Min-Jung,Kim, Yoon-Jung,Kim, Sungdae,Nahm, Minyeop,Oh, Soo-Jin,Kim, Hyun-Man,Yim, Jeongbin,Lee, C. Justin,Bae, Yong Chul,Lee, Seungbok Elsevier 2009 Developmental Biology Vol.330 No.2
<P><B>Abstract</B></P><P>Hereditary spastic paraplegia (HSP) is an inherited neurological disorder characterized by progressive spasticity and weakness of the lower extremities. The most common early-onset form of HSP is caused by mutations in the human gene that encodes the dynamin-family GTPase Atlastin-1 (Atl-1). Recently, loss of the <I>Drosophila</I> ortholog of Atl-1 (Atl) has been found to induce locomotor impairments from the earliest adult stages, suggesting the developmental role of atlastin-subfamily GTPases. Here, we provide evidence that Atl is required for normal growth of muscles and synapses at the neuromuscular junction (NMJ). Atl protein is highly expressed in larval body-wall muscles. Loss-of-function mutations in the <I>atl</I> gene reduce the size of muscles and increase the number of synaptic boutons. Rescue of these defects is accomplished by muscular, but not neuronal expression of Atl. Loss of Atl also disrupts ER and Golgi morphogenesis in muscles and reduces the synaptic levels of the scaffold proteins Dlg and α-spectrin. We also provide evidence that Atl functions with the microtubule-severing protein Spastin to disassemble microtubules in muscles. Finally, we demonstrate that the microtubule-destabilizing drug vinblastine alleviates synapse and muscle defects in <I>atl</I> mutants. Together, our results suggest that Atl controls synapse development and ER and Golgi morphogenesis by regulating microtubule stability.</P>
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