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1.
FASEB J ; 36 Suppl 12022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35554493

RESUMO

Caveolae are 60-100 nm sized bulb-shaped plasma membrane invaginations found in various cell types including adipocytes, endothelial cells and myocytes. Their cellular functions comprise endocytosis and signaling processes, cellular lipid uptake, as well as sensing and regulation of membrane tension. Thereby, it was shown previously that caveolae can change their membrane shape from invaginated bulbs to flat domains and vice versa. However it is currently not clear which proteins are responsible for the membrane curvature changes. Here, we report the first detailed structural investigation of caveolae membrane shapes in vivo. To do so, Platinum replica EM images of the plasma membrane in mouse embryonic fibroblasts and endothelial cells were correlated to super-resolution (STED) fluorescence intensities of proteins associated with caveolae domains. This correlative imaging approach (CLEM) allowed us to precisely localize caveolae related proteins to the underlying membrane curvature. The major structural caveolae proteins such as Caveolins and Cavins were found in all caveolae membrane domains independent of their curvature. Surprisingly, EHD2, a caveolar neck protein, was not only detected at bulb-shaped invaginations but also at flat caveolae. Contrarily, Pacsin/Syndapin2 and EHBP1 were predominantly surrounding flat caveolae domains indicating that both proteins promote the neck formation. Because dynamin was previously associated with caveolae endocytosis and mobility we analyzed its spatial distribution to caveolae. However, our detailed CLEM analysis failed to determine dynamin to caveolae membrane domains in several cell types. Additionally, dynamin lacking cells did not show severe morphological changes of caveolae suggesting that dynamin is not involved in caveolae membrane curvature changes. Taken together, this study gives novel insights in caveolae structure and their formation from flat to invaginated membrane domains.

2.
Nat Struct Mol Biol ; 29(3): 218-228, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35256802

RESUMO

Phosphatidylinositol 3-kinase type 2α (PI3KC2α) is an essential member of the structurally unresolved class II PI3K family with crucial functions in lipid signaling, endocytosis, angiogenesis, viral replication, platelet formation and a role in mitosis. The molecular basis of these activities of PI3KC2α is poorly understood. Here, we report high-resolution crystal structures as well as a 4.4-Å cryogenic-electron microscopic (cryo-EM) structure of PI3KC2α in active and inactive conformations. We unravel a coincident mechanism of lipid-induced activation of PI3KC2α at membranes that involves large-scale repositioning of its Ras-binding and lipid-binding distal Phox-homology and C-C2 domains, and can serve as a model for the entire class II PI3K family. Moreover, we describe a PI3KC2α-specific helical bundle domain that underlies its scaffolding function at the mitotic spindle. Our results advance our understanding of PI3K biology and pave the way for the development of specific inhibitors of class II PI3K function with wide applications in biomedicine.


Assuntos
Fosfatidilinositol 3-Quinase , Fosfatidilinositol 3-Quinases , Endocitose , Lipídeos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais
3.
EMBO J ; 41(9): e109352, 2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35318705

RESUMO

Neural circuit function requires mechanisms for controlling neurotransmitter release and the activity of neuronal networks, including modulation by synaptic contacts, synaptic plasticity, and homeostatic scaling. However, how neurons intrinsically monitor and feedback control presynaptic neurotransmitter release and synaptic vesicle (SV) recycling to restrict neuronal network activity remains poorly understood at the molecular level. Here, we investigated the reciprocal interplay between neuronal endosomes, organelles of central importance for the function of synapses, and synaptic activity. We show that elevated neuronal activity represses the synthesis of endosomal lipid phosphatidylinositol 3-phosphate [PI(3)P] by the lipid kinase VPS34. Neuronal activity in turn is regulated by endosomal PI(3)P, the depletion of which reduces neurotransmission as a consequence of perturbed SV endocytosis. We find that this mechanism involves Calpain 2-mediated hyperactivation of Cdk5 downstream of receptor- and activity-dependent calcium influx. Our results unravel an unexpected function for PI(3)P-containing neuronal endosomes in the control of presynaptic vesicle cycling and neurotransmission, which may explain the involvement of the PI(3)P-producing VPS34 kinase in neurological disease and neurodegeneration.


Assuntos
Transmissão Sináptica , Vesículas Sinápticas , Endocitose/fisiologia , Endossomos , Neurotransmissores , Fosfatos de Fosfatidilinositol , Sinapses/fisiologia , Transmissão Sináptica/fisiologia
4.
J Biol Chem ; 298(3): 101740, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35182526

RESUMO

Lysosomes serve as dynamic regulators of cell and organismal physiology by integrating the degradation of macromolecules with receptor and nutrient signaling. Previous studies have established that activation of the transcription factor EB (TFEB) and transcription factor E3 (TFE3) induces the expression of lysosomal genes and proteins in signaling-inactive starved cells, that is, under conditions when activity of the master regulator of nutrient-sensing signaling mechanistic target of rapamycin complex 1 is repressed. How lysosome biogenesis is triggered in signaling-active cells is incompletely understood. Here, we identify a role for calcium release from the lumen of the endoplasmic reticulum in the control of lysosome biogenesis that is independent of mechanistic target of rapamycin complex 1. We show using functional imaging that calcium efflux from endoplasmic reticulum stores induced by inositol triphosphate accumulation upon depletion of inositol polyphosphate-5-phosphatase A, an inositol 5-phosphatase downregulated in cancer and defective in spinocerebellar ataxia, or receptor-mediated phospholipase C activation leads to the induction of lysosome biogenesis. This mechanism involves calcineurin and the nuclear translocation and elevated transcriptional activity of TFEB/TFE3. Our findings reveal a crucial function for inositol polyphosphate-5-phosphatase A-mediated triphosphate hydrolysis in the control of lysosome biogenesis via TFEB/TFE3, thereby contributing to our understanding how cells are able to maintain their lysosome content under conditions of active receptor and nutrient signaling.


Assuntos
Autofagia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Cálcio , Retículo Endoplasmático , Lisossomos , Polifosfatos , Autofagia/fisiologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Calcineurina/metabolismo , Cálcio/metabolismo , Retículo Endoplasmático/metabolismo , Inositol/metabolismo , Lisossomos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Polifosfatos/metabolismo
5.
Org Biomol Chem ; 2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35188523

RESUMO

The (in)ability to permeate membranes is a key feature of chemical biology probes that defines their suitability for specific applications. Here we report sulfonated rhodamines that endow xanthene dyes with cellular impermeability for analysis of surface proteins. We fuse charged sulfonates to red and far-red dyes to obtain Sulfo549 and Sulfo646, respectively, and further link these to benzylguanine and choloralkane substrates for SNAP-tag and Halo-tag labelling. Sulfonated rhodamine-conjugated fluorophores maintain desirable photophysical properties, such as brightness and photostability. While transfected cells with a nuclear localized SNAP-tag remain unlabelled, extracellular exposed tags can be cleanly visualized. By multiplexing with a permeable rhodamine, we are able to differentiate extra- and intracellular SNAP- and Halo-tags, including those installed on the glucagon-like peptide-1 receptor, a prototypical class B G protein-coupled receptor. Sulfo549 and Sulfo646 also labelled transfected neurons derived from induced pluripotent stem cells (iPSCs), allowing STED nanoscopy of the axonal membrane. Together, this work provides a new avenue for rendering dyes impermeable for exclusive extracellular visualization via self-labelling protein tags. We anticipate that Sulfo549, Sulfo646 and their congeners will be useful for a number of cell biology applications where labelling of intracellular sites interferes with accurate surface protein analysis.

7.
Adv Sci (Weinh) ; 9(9): e2103249, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35098698

RESUMO

Breast cancer is the most prevalent cancer and a major cause of death in women worldwide. Although early diagnosis and therapeutic intervention significantly improve patient survival rate, metastasis still accounts for most deaths. Here it is reported that, in a cohort of more than 2000 patients with breast cancer, overexpression of PI3KC2α occurs in 52% of cases and correlates with high tumor grade as well as increased probability of distant metastatic events, irrespective of the subtype. Mechanistically, it is demonstrated that PI3KC2α synthetizes a pool of PI(3,4)P2 at focal adhesions that lowers their stability and directs breast cancer cell migration, invasion, and metastasis. PI(3,4)P2 locally produced by PI3KC2α at focal adhesions recruits the Ras GTPase activating protein 3 (RASA3), which inactivates R-RAS, leading to increased focal adhesion turnover, migration, and invasion both in vitro and in vivo. Proof-of-concept is eventually provided that inhibiting PI3KC2α or lowering RASA3 activity at focal adhesions significantly reduces the metastatic burden in PI3KC2α-overexpressing breast cancer, thereby suggesting a novel strategy for anti-breast cancer therapy.


Assuntos
Neoplasias da Mama , Adesão Celular/fisiologia , Feminino , Adesões Focais/metabolismo , Adesões Focais/patologia , Proteínas Ativadoras de GTPase/metabolismo , Humanos , Fosfatidilinositóis/metabolismo
8.
Elife ; 112022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-35014951

RESUMO

Neurotransmission is based on the exocytic fusion of synaptic vesicles (SVs) followed by endocytic membrane retrieval and the reformation of SVs. Conflicting models have been proposed regarding the mechanisms of SV endocytosis, most notably clathrin/adaptor protein complex 2 (AP-2)-mediated endocytosis and clathrin-independent ultrafast endocytosis. Partitioning between these pathways has been suggested to be controlled by temperature and stimulus paradigm. We report on the comprehensive survey of six major SV proteins to show that SV endocytosis in mouse hippocampal neurons at physiological temperature occurs independent of clathrin while the endocytic retrieval of a subset of SV proteins including the vesicular transporters for glutamate and GABA depend on sorting by the clathrin adaptor AP-2. Our findings highlight a clathrin-independent role of the clathrin adaptor AP-2 in the endocytic retrieval of select SV cargos from the presynaptic cell surface and suggest a revised model for the endocytosis of SV membranes at mammalian central synapses.


Assuntos
Complexo 2 de Proteínas Adaptadoras/genética , Clatrina/metabolismo , Endocitose , Sinapses/fisiologia , Complexo 2 de Proteínas Adaptadoras/metabolismo , Animais , Camundongos
9.
Science ; 374(6573): eabk0410, 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34882480

RESUMO

Cytokinetic membrane abscission is a spatially and temporally regulated process that requires ESCRT (endosomal sorting complexes required for transport)­dependent control of membrane remodeling at the midbody, a subcellular organelle that defines the cleavage site. Alteration of ESCRT function can lead to cataract, but the underlying mechanism and its relation to cytokinesis are unclear. We found a lens-specific cytokinetic process that required PI3K-C2α (phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2α), its lipid product PI(3,4)P2 (phosphatidylinositol 3,4-bisphosphate), and the PI(3,4)P2­binding ESCRT-II subunit VPS36 (vacuolar protein-sorting-associated protein 36). Loss of each of these components led to impaired cytokinesis, triggering premature senescence in the lens of fish, mice, and humans. Thus, an evolutionarily conserved pathway underlies the cell type­specific control of cytokinesis that helps to prevent early onset cataract by protecting from senescence.


Assuntos
Catarata/patologia , Senescência Celular , Citocinese , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Cristalino/citologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositóis/metabolismo , Senilidade Prematura , Animais , Evolução Biológica , Proteínas de Ligação ao Cálcio/metabolismo , Catarata/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Humanos , Cristalino/crescimento & desenvolvimento , Cristalino/metabolismo , Camundongos , Mutação , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 4,5-Difosfato/metabolismo , Tubulina (Proteína)/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
10.
Chem Sci ; 12(32): 10696-10702, 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34476054

RESUMO

Inositol poly- and pyrophosphates (InsPs and PP-InsPs) are densely phosphorylated eukaryotic messengers, which are involved in numerous cellular processes. To elucidate their signaling functions at the molecular level, non-hydrolyzable bisphosphonate analogs of inositol pyrophosphates, PCP-InsPs, have been instrumental. Here, an efficient synthetic strategy to obtain these analogs in unprecedented quantities is described - relying on the use of combined phosphate ester-phosphoramidite reagents. The PCP-analogs, alongside their natural counterparts, were applied to investigate their regulatory effect on insulin-degrading enzyme (IDE), using a range of biochemical, biophysical and computational methods. A unique interplay between IDE, its substrates and the PP-InsPs was uncovered, in which the PP-InsPs differentially modulated the activity of the enzyme towards short peptide substrates. Aided by molecular docking and molecular dynamics simulations, a flexible binding mode for the InsPs/PP-InsPs was identified at the anion binding site of IDE. Targeting IDE for therapeutic purposes should thus take regulation by endogenous PP-InsP metabolites into account.

11.
Dev Cell ; 56(11): 1557-1559, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34102102

RESUMO

In this issue of Developmental Cell, Kamalesh et al. (2021) reveal a mechanochemical mechanism for the coupling of exocytic release of secretory granule content with endocytic membrane retrieval via actomyosin-driven membrane folding.


Assuntos
Transporte Biológico
12.
Nat Commun ; 12(1): 2673, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976123

RESUMO

Vesicular traffic and membrane contact sites between organelles enable the exchange of proteins, lipids, and metabolites. Recruitment of tethers to contact sites between the endoplasmic reticulum (ER) and the plasma membrane is often triggered by calcium. Here we reveal a function for calcium in the repression of cholesterol export at membrane contact sites between the ER and the Golgi complex. We show that calcium efflux from ER stores induced by inositol-triphosphate [IP3] accumulation upon loss of the inositol 5-phosphatase INPP5A or receptor signaling triggers depletion of cholesterol and associated Gb3 from the cell surface, resulting in a blockade of clathrin-independent endocytosis (CIE) of Shiga toxin. This phenotype is caused by the calcium-induced dissociation of oxysterol binding protein (OSBP) from the Golgi complex and from VAP-containing membrane contact sites. Our findings reveal a crucial function for INPP5A-mediated IP3 hydrolysis in the control of lipid exchange at membrane contact sites.


Assuntos
Cálcio/metabolismo , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Fosfatos de Inositol/metabolismo , Lipídeos de Membrana/metabolismo , Animais , Transporte Biológico , Células COS , Chlorocebus aethiops , Colesterol/metabolismo , Endocitose , Células HEK293 , Células HeLa , Humanos , Inositol Polifosfato 5-Fosfatases/genética , Inositol Polifosfato 5-Fosfatases/metabolismo , Microscopia Confocal , Fosfatos de Fosfatidilinositol/metabolismo , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Triexosilceramidas/metabolismo
14.
Proc Natl Acad Sci U S A ; 118(10)2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33653949

RESUMO

Charcot-Marie-Tooth type 4B1 (CMT4B1) is a severe autosomal recessive demyelinating neuropathy with childhood onset, caused by loss-of-function mutations in the myotubularin-related 2 (MTMR2) gene. MTMR2 is a ubiquitously expressed catalytically active 3-phosphatase, which in vitro dephosphorylates the 3-phosphoinositides PtdIns3P and PtdIns(3,5)P 2, with a preference for PtdIns(3,5)P 2 A hallmark of CMT4B1 neuropathy are redundant loops of myelin in the nerve termed myelin outfoldings, which can be considered the consequence of altered growth of myelinated fibers during postnatal development. How MTMR2 loss and the resulting imbalance of 3'-phosphoinositides cause CMT4B1 is unknown. Here we show that MTMR2 by regulating PtdIns(3,5)P 2 levels coordinates mTORC1-dependent myelin synthesis and RhoA/myosin II-dependent cytoskeletal dynamics to promote myelin membrane expansion and longitudinal myelin growth. Consistent with this, pharmacological inhibition of PtdIns(3,5)P 2 synthesis or mTORC1/RhoA signaling ameliorates CMT4B1 phenotypes. Our data reveal a crucial role for MTMR2-regulated lipid turnover to titrate mTORC1 and RhoA signaling thereby controlling myelin growth.


Assuntos
Doença de Charcot-Marie-Tooth/metabolismo , Bainha de Mielina/metabolismo , Fosfatos de Fosfatidilinositol/biossíntese , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Transdução de Sinais , Animais , Doença de Charcot-Marie-Tooth/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Knockout , Bainha de Mielina/genética , Miosina Tipo II/genética , Miosina Tipo II/metabolismo , Fosfatos de Fosfatidilinositol/genética , Proteínas Tirosina Fosfatases não Receptoras/genética , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
15.
Curr Opin Neurobiol ; 69: 76-83, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33744822

RESUMO

Neurons are long-lived cells with a complex architecture, in which synapses may be located far away from the cell body and are subject to plastic changes, thereby posing special challenges to the systems that maintain and dynamically regulate the synaptic proteome. These mechanisms include neuronal autophagy and the endolysosome pathway, as well as the ubiquitin/proteasome system, which cooperate in the constitutive and regulated turnover of presynaptic and postsynaptic proteins. Here, we summarize the pathways involved in synaptic protein degradation and the mechanisms underlying their regulation, for example, by neuronal activity, with an emphasis on the presynaptic compartment and outline perspectives for future research. Keywords: Synapse, Synaptic vesicle, Autophagy, Endolysosome, Proteasome, Protein turnover, Protein degradation, Endosome, Lysosome.


Assuntos
Neurônios , Sinapses , Neurônios/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Sinapses/metabolismo , Transmissão Sináptica , Ubiquitina/metabolismo
16.
Autophagy ; 17(4): 1049-1051, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33615987

RESUMO

Neurons are long-lived cells that communicate via release of neurotransmitter at specialized contacts termed synapses. The maintenance of neuronal health and the regulation of synaptic function requires the efficient removal of damaged or dispensable proteins and organelles from synapses. How macroautophagy/autophagy contributes to neuronal and synaptic protein turnover, and what its main physiological substrates are in healthy neurons is largely unknown. We have now shown that loss of neuronal autophagy facilitates presynaptic neurotransmission by controlling the axonal endoplasmic reticulum and, thereby, axonal and synaptic calcium homeostasis.


Assuntos
Autofagia , Estresse do Retículo Endoplasmático , Retículo Endoplasmático , Neurônios , Transmissão Sináptica
17.
FEBS J ; 288(24): 7025-7042, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33387369

RESUMO

The phosphoinositide 3-kinase (PI3K) family of lipid-modifying enzymes plays vital roles in cell signaling and membrane trafficking through the production of 3-phosphorylated phosphoinositides. Numerous studies have analyzed the structure and function of class I and class III PI3Ks. In contrast, we know comparably little about the structure and physiological functions of the class II enzymes. Only recent studies have begun to unravel their roles in development, endocytic and endolysosomal membrane dynamics, signal transduction, and cell migration, while the mechanisms that control their localization and enzymatic activity remain largely unknown. Here, we summarize our current knowledge of the class II PI3Ks and outline open questions related to their structure, enzymatic activity, and their physiological and pathophysiological functions.


Assuntos
Células Secretoras de Insulina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Animais , Movimento Celular , Humanos , Transdução de Sinais
18.
Neuron ; 109(1): 27-41, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33098763

RESUMO

Neurons are highly polarized cells with a single axon and multiple dendrites derived from the cell body to form tightly associated pre- and postsynaptic compartments. As the biosynthetic machinery is largely restricted to the somatodendritic domain, the vast majority of presynaptic components are synthesized in the neuronal soma, packaged into synaptic precursor vesicles, and actively transported along the axon to sites of presynaptic biogenesis. In contrast with the significant progress that has been made in understanding synaptic transmission and processing of information at the post-synapse, comparably little is known about the formation and dynamic remodeling of the presynaptic compartment. We review here our current understanding of the mechanisms that govern the biogenesis, transport, and assembly of the key components for presynaptic neurotransmission, discuss how alterations in presynaptic assembly may impact nervous system function or lead to disease, and outline key open questions for future research.


Assuntos
Neurogênese/fisiologia , Terminações Pré-Sinápticas/metabolismo , Transporte Proteico/fisiologia , Sinapses/metabolismo , Animais , Humanos , Terminações Pré-Sinápticas/ultraestrutura , Sinapses/ultraestrutura , Transmissão Sináptica/fisiologia , Vesículas Sinápticas/metabolismo , Vesículas Sinápticas/ultraestrutura
19.
Neuron ; 109(2): 299-313.e9, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33157003

RESUMO

Neurons are known to rely on autophagy for removal of defective proteins or organelles to maintain synaptic neurotransmission and counteract neurodegeneration. In spite of its importance for neuronal health, the physiological substrates of neuronal autophagy in the absence of proteotoxic challenge have remained largely elusive. We use knockout mice conditionally lacking the essential autophagy protein ATG5 and quantitative proteomics to demonstrate that loss of neuronal autophagy causes selective accumulation of tubular endoplasmic reticulum (ER) in axons, resulting in increased excitatory neurotransmission and compromised postnatal viability in vivo. The gain in excitatory neurotransmission is shown to be a consequence of elevated calcium release from ER stores via ryanodine receptors accumulated in axons and at presynaptic sites. We propose a model where neuronal autophagy controls axonal ER calcium stores to regulate neurotransmission in healthy neurons and in the brain.


Assuntos
Autofagia/fisiologia , Axônios/fisiologia , Retículo Endoplasmático/fisiologia , Neurônios/fisiologia , Terminações Pré-Sinápticas/fisiologia , Animais , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/citologia , Hipocampo/fisiologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Transmissão Sináptica/fisiologia
20.
J Neurochem ; 158(3): 589-602, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33372296

RESUMO

Neurons, because of their elaborate morphology and the long distances between distal axons and the soma as well as their longevity, pose special challenges to autophagy and to the endolysosomal system, two of the main degradative routes for turnover of defective proteins and organelles. Autophagosomes sequester cytoplasmic or organellar cargos by engulfing them into their lumen before fusion with degradative lysosomes enriched in neuronal somata and participate in retrograde signaling to the soma. Endosomes are mainly involved in the sorting, recycling, or lysosomal turnover of internalized or membrane-bound macromolecules to maintain axonal membrane homeostasis. Lysosomes and the multiple shades of lysosome-related organelles also serve non-degradative roles, for example, in nutrient signaling and in synapse formation. Recent years have begun to shed light on the distinctive organization of the autophagy and endolysosomal systems in neurons, in particular their roles in axons. We review here our current understanding of the localization, distribution, and growing list of functions of these organelles in the axon in health and disease and outline perspectives for future research.


Assuntos
Autofagossomos/metabolismo , Autofagia/fisiologia , Axônios/metabolismo , Endossomos/metabolismo , Lisossomos/metabolismo , Animais , Autofagossomos/genética , Endossomos/genética , Humanos , Lisossomos/genética , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Neurônios/metabolismo , Transporte Proteico/fisiologia
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