The Journey of the Synaptic Autophagosome: A Cell Biological Perspective
2020; Cell Press; Volume: 105; Issue: 6 Linguagem: Inglês
10.1016/j.neuron.2020.01.018
ISSN1097-4199
AutoresSarah E. Hill, Daniel A. Colón‐Ramos,
Tópico(s)Cellular transport and secretion
ResumoAutophagy is a key cellular degradative pathway, important for neuronal homeostasis and function. Disruption of autophagy is associated with neuronal dysfunction and neurodegeneration. Autophagy is compartmentalized in neurons, with specific stages of the pathway occurring in distinct subcellular compartments. Coordination of these stages drives progression of autophagy and enables clearance of substrates. Yet, we are only now learning how these distributed processes are integrated across the neuron. In this review, we focus on the cell biological course of autophagy in neurons, from biogenesis at the synapse to degradation in the soma. We describe how the steps of autophagy are distributed across neuronal subcellular compartments, how local machinery regulates autophagy, and the impact of coordinated regulation on neuronal physiology and disease. We also discuss how recent advances in our understanding of neuronal autophagic mechanisms have reframed how we think about the role of local regulation of autophagy in all tissues. Autophagy is a key cellular degradative pathway, important for neuronal homeostasis and function. Disruption of autophagy is associated with neuronal dysfunction and neurodegeneration. Autophagy is compartmentalized in neurons, with specific stages of the pathway occurring in distinct subcellular compartments. Coordination of these stages drives progression of autophagy and enables clearance of substrates. Yet, we are only now learning how these distributed processes are integrated across the neuron. In this review, we focus on the cell biological course of autophagy in neurons, from biogenesis at the synapse to degradation in the soma. We describe how the steps of autophagy are distributed across neuronal subcellular compartments, how local machinery regulates autophagy, and the impact of coordinated regulation on neuronal physiology and disease. We also discuss how recent advances in our understanding of neuronal autophagic mechanisms have reframed how we think about the role of local regulation of autophagy in all tissues. Macroautophagy, hereafter autophagy, is a cellular degradative pathway, important for development and for maintenance of cellular homeostasis. In neurons, autophagy has been implicated in development, physiology, and aging (Azarnia Tehran et al., 2018Azarnia Tehran D. Kuijpers M. Haucke V. Presynaptic endocytic factors in autophagy and neurodegeneration.Curr. Opin. Neurobiol. 2018; 48: 153-159Crossref PubMed Scopus (15) Google Scholar, Kulkarni et al., 2018Kulkarni A. Chen J. Maday S. Neuronal autophagy and intercellular regulation of homeostasis in the brain.Curr. Opin. Neurobiol. 2018; 51: 29-36Crossref PubMed Scopus (0) Google Scholar, Liang and Sigrist, 2018Liang Y. Sigrist S. Autophagy and proteostasis in the control of synapse aging and disease.Curr. Opin. Neurobiol. 2018; 48: 113-121Crossref PubMed Scopus (24) Google Scholar, Lüningschrör and Sendtner, 2018Lüningschrör P. Sendtner M. Autophagy in the presynaptic compartment.Curr. Opin. Neurobiol. 2018; 51: 80-85Crossref PubMed Scopus (4) Google Scholar, Menzies et al., 2017Menzies F.M. Fleming A. Caricasole A. Bento C.F. Andrews S.P. Ashkenazi A. Füllgrabe J. Jackson A. Jimenez Sanchez M. Karabiyik C. et al.Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities.Neuron. 2017; 93: 1015-1034Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar, Stavoe and Holzbaur, 2019Stavoe A.K.H. Holzbaur E.L.F. Autophagy in Neurons.Annu. Rev. Cell Dev. Biol. 2019; 35: 477-500Crossref PubMed Scopus (15) Google Scholar, Vijayan and Verstreken, 2017Vijayan V. Verstreken P. Autophagy in the presynaptic compartment in health and disease.J. Cell Biol. 2017; 216: 1895-1906Crossref PubMed Scopus (60) Google Scholar). While most of the studies examining synaptic autophagy have focused on autophagosomes in axons, autophagy has also been observed to occur in the neuronal soma and the dendrites. In this review, we discuss how the cell biology of the neuron impacts the journey of the synaptic autophagosome, from biogenesis to breakdown. We begin with a brief synopsis of the autophagy pathway, focused on its importance in neuronal health and disease and how its regulation is uniquely adapted in neurons to meet their needs. Autophagy is essential for neuronal physiology and survival. Neurons rely on autophagy to efficiently remove cellular debris and toxic materials, with imbalances leading to neuron death. Neuron-specific depletion of autophagy in mice results in axon degeneration, accumulation of ubiquitin-containing protein aggregates, and neuronal cell death (Hara et al., 2006Hara T. Nakamura K. Matsui M. Yamamoto A. Nakahara Y. Suzuki-Migishima R. Yokoyama M. Mishima K. Saito I. Okano H. Mizushima N. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice.Nature. 2006; 441: 885-889Crossref PubMed Scopus (2666) Google Scholar, Komatsu et al., 2006Komatsu M. Waguri S. Chiba T. Murata S. Iwata J. Tanida I. Ueno T. Koike M. Uchiyama Y. Kominami E. Tanaka K. Loss of autophagy in the central nervous system causes neurodegeneration in mice.Nature. 2006; 441: 880-884Crossref PubMed Scopus (2444) Google Scholar, Komatsu et al., 2007Komatsu M. Wang Q.J. Holstein G.R. Friedrich Jr., V.L. Iwata J. Kominami E. Chait B.T. Tanaka K. Yue Z. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration.Proc. Natl. Acad. Sci. USA. 2007; 104: 14489-14494Crossref PubMed Scopus (412) Google Scholar). These findings underscore the importance of autophagy for neuronal physiology and function. Autophagy has also been implicated in human neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. For example, neurons from Alzheimer’s and Parkinson’s disease patients show an abnormal accumulation of autophagosomes in distal neuronal processes and at synaptic terminals (Gowrishankar et al., 2015Gowrishankar S. Yuan P. Wu Y. Schrag M. Paradise S. Grutzendler J. De Camilli P. Ferguson S.M. Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques.Proc. Natl. Acad. Sci. USA. 2015; 112: E3699-E3708Crossref PubMed Scopus (134) Google Scholar, Nixon et al., 2005Nixon R.A. Wegiel J. Kumar A. Yu W.H. Peterhoff C. Cataldo A. Cuervo A.M. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study.J. Neuropathol. Exp. Neurol. 2005; 64: 113-122Crossref PubMed Google Scholar, Tammineni et al., 2017Tammineni P. Ye X. Feng T. Aikal D. Cai Q. Impaired retrograde transport of axonal autophagosomes contributes to autophagic stress in Alzheimer’s disease neurons.eLife. 2017; 6: e21776Crossref PubMed Scopus (42) Google Scholar, Yue et al., 2009Yue Z. Friedman L. Komatsu M. Tanaka K. The cellular pathways of neuronal autophagy and their implication in neurodegenerative diseases.Biochim. Biophys. Acta. 2009; 1793: 1496-1507Crossref PubMed Scopus (129) Google Scholar). Emerging evidence supports that loss of lysosomal function may act as a primary disease mechanism contributing to neuronal death (Wallings et al., 2019Wallings R.L. Humble S.W. Ward M.E. Wade-Martins R. Lysosomal Dysfunction at the Centre of Parkinson’s Disease and Frontotemporal Dementia/Amyotrophic Lateral Sclerosis.Trends Neurosci. 2019; 42: 899-912Abstract Full Text Full Text PDF PubMed Google Scholar). Autophagic and lysosomal markers have been proposed as biomarkers for disease detection (Mputhia et al., 2019Mputhia Z. Hone E. Tripathi T. Sargeant T. Martins R. Bharadwaj P. Autophagy Modulation as a Treatment of Amyloid Diseases.Molecules. 2019; 24https://doi.org/10.3390/molecules24183372Crossref PubMed Scopus (15) Google Scholar), and a growing number of pharmacological agents seek to modulate the autophagy pathway as a therapeutic intervention for neurodegenerative diseases associated with autophagy (Malik et al., 2019Malik B.R. Maddison D.C. Smith G.A. Peters O.M. Autophagic and endo-lysosomal dysfunction in neurodegenerative disease.Mol. Brain. 2019; 12: 100Crossref PubMed Scopus (1) Google Scholar). But while much evidence supports the idea that defects in autophagy contribute to neurodegenerative diseases, the pathogenic mechanisms that directly link the steps of autophagy to disease outcomes are not fully understood. For instance, excessive autophagy can contribute to neuronal stress, but loss of degradative activity can also prevent the removal of toxic substrates, affect neuronal physiology, and contribute to disease (Malik et al., 2019Malik B.R. Maddison D.C. Smith G.A. Peters O.M. Autophagic and endo-lysosomal dysfunction in neurodegenerative disease.Mol. Brain. 2019; 12: 100Crossref PubMed Scopus (1) Google Scholar). Moreover, in neurons, autophagic organelle biogenesis, transport, and degradation occur in varied subcellular compartments, and these local environments impact neuronal autophagy. In this review, we describe our current understanding of the cell biology of autophagy in axons, focusing on biogenesis events at presynaptic sites, trafficking along axons, fusion with late endosomes/lysosomes for degradation, and the orchestrated regulation of these processes across subcellular compartments during neuronal autophagy. Understanding how autophagic cargo engulfment coordinates with lysosomal degradation across the structure of the neuron will be important to link the mechanisms of autophagy with neurodegenerative diseases during autophagy dysfunction. Most of our understanding of autophagy has come from studies conducted in non-neuronal cells. Autophagy was first discovered in yeast as a mechanism to support biosynthesis under nutrient deprivation by degrading and reusing cellular materials (Mizushima and Komatsu, 2011Mizushima N. Komatsu M. Autophagy: renovation of cells and tissues.Cell. 2011; 147: 728-741Abstract Full Text Full Text PDF PubMed Scopus (2738) Google Scholar, Tsukada and Ohsumi, 1993Tsukada M. Ohsumi Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae.FEBS Lett. 1993; 333: 169-174Crossref PubMed Scopus (1169) Google Scholar, Wen and Klionsky, 2016Wen X. Klionsky D.J. An overview of macroautophagy in yeast.J. Mol. Biol. 2016; 428: 1681-1699Crossref PubMed Scopus (99) Google Scholar). First, double-membrane structures, called autophagosomes, form around cellular cargoes such as aged organelles or proteins and then fuse with proteolytic late endosomes or lysosomes to mediate degradation. Autophagy is regulated by a series of protein complexes, which include 30+ proteins involved in processes from biogenesis of autophagosomes and cargo recognition to transport and degradation. The core enzymatic processes of autophagy are evolutionarily conserved and are necessary for autophagy in neurons. However, the signals inducing autophagy, the physiological roles for autophagy, and autophagy’s subcellular distribution in neurons are distinct. Processes associated with neuronal function, such as synaptic transmission, are linked to the regulation of autophagy in neurons (Hernandez et al., 2012Hernandez D. Torres C.A. Setlik W. Cebrián C. Mosharov E.V. Tang G. Cheng H.C. Kholodilov N. Yarygina O. Burke R.E. et al.Regulation of presynaptic neurotransmission by macroautophagy.Neuron. 2012; 74: 277-284Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, Shehata et al., 2012Shehata M. Matsumura H. Okubo-Suzuki R. Ohkawa N. Inokuchi K. Neuronal stimulation induces autophagy in hippocampal neurons that is involved in AMPA receptor degradation after chemical long-term depression.J. Neurosci. 2012; 32: 10413-10422Crossref PubMed Scopus (138) Google Scholar, Soukup et al., 2016Soukup S.F. Kuenen S. Vanhauwaert R. Manetsberger J. Hernández-Díaz S. Swerts J. Schoovaerts N. Vilain S. Gounko N.V. Vints K. et al.A LRRK2-Dependent EndophilinA Phosphoswitch Is Critical for Macroautophagy at Presynaptic Terminals.Neuron. 2016; 92: 829-844Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, Wang et al., 2015Wang T. Martin S. Papadopulos A. Harper C.B. Mavlyutov T.A. Niranjan D. Glass N.R. Cooper-White J.J. Sibarita J.B. Choquet D. et al.Control of autophagosome axonal retrograde flux by presynaptic activity unveiled using botulinum neurotoxin type a.J. Neurosci. 2015; 35: 6179-6194Crossref PubMed Scopus (58) Google Scholar). Neuronal autophagy has been linked to and shown to influence processes like neurotransmitter receptor turnover (Rowland et al., 2006Rowland A.M. Richmond J.E. Olsen J.G. Hall D.H. Bamber B.A. Presynaptic terminals independently regulate synaptic clustering and autophagy of GABAA receptors in Caenorhabditis elegans.J. Neurosci. 2006; 26: 1711-1720Crossref PubMed Scopus (104) Google Scholar), synaptic development (Shen and Ganetzky, 2009Shen W. Ganetzky B. Autophagy promotes synapse development in Drosophila.J. Cell Biol. 2009; 187: 71-79Crossref PubMed Scopus (149) Google Scholar, Stavoe et al., 2016Stavoe A.K. Hill S.E. Hall D.H. Colón-Ramos D.A. KIF1A/UNC-104 Transports ATG-9 to Regulate Neurodevelopment and Autophagy at Synapses.Dev. Cell. 2016; 38: 171-185Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar), synaptic pruning (Tang et al., 2014Tang G. Gudsnuk K. Kuo S.H. Cotrina M.L. Rosoklija G. Sosunov A. Sonders M.S. Kanter E. Castagna C. Yamamoto A. et al.Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits.Neuron. 2014; 83: 1131-1143Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar), and synaptic plasticity (Glatigny et al., 2019Glatigny M. Moriceau S. Rivagorda M. Ramos-Brossier M. Nascimbeni A.C. Lante F. Shanley M.R. Boudarene N. Rousseaud A. Friedman A.K. et al.Autophagy Is Required for Memory Formation and Reverses Age-Related Memory Decline.Curr. Biol. 2019; 29 (435–448)Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, Nikoletopoulou et al., 2017Nikoletopoulou V. Sidiropoulou K. Kallergi E. Dalezios Y. Tavernarakis N. Modulation of Autophagy by BDNF Underlies Synaptic Plasticity.Cell Metab. 2017; 26: 230-242Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar), among other processes essential for neuronal physiology. The steps of autophagy are modified to fit the context of the polarized neuron and the substrates within the neuron being targeted for degradation. For example, one of the most striking aspects of neuronal autophagy is its spatial organization. Autophagosomes form in distal axonal compartments near synapses and undergo retrograde transport. During transport, they fuse with late endosomes and lysosomes before their cargo is degraded in the cell body (Bunge, 1973Bunge M.B. Fine structure of nerve fibers and growth cones of isolated sympathetic neurons in culture.J. Cell Biol. 1973; 56: 713-735Crossref PubMed Google Scholar, Katsumata et al., 2010Katsumata K. Nishiyama J. Inoue T. Mizushima N. Takeda J. Yuzaki M. Dynein- and activity-dependent retrograde transport of autophagosomes in neuronal axons.Autophagy. 2010; 6: 378-385Crossref PubMed Scopus (45) Google Scholar, Lee et al., 2011Lee S. Sato Y. Nixon R.A. Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer’s-like axonal dystrophy.J. Neurosci. 2011; 31: 7817-7830Crossref PubMed Scopus (254) Google Scholar, Maday et al., 2012Maday S. Wallace K.E. Holzbaur E.L. Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons.J. Cell Biol. 2012; 196: 407-417Crossref PubMed Scopus (312) Google Scholar, Ravikumar et al., 2005Ravikumar B. Acevedo-Arozena A. Imarisio S. Berger Z. Vacher C. O’Kane C.J. Brown S.D. Rubinsztein D.C. Dynein mutations impair autophagic clearance of aggregate-prone proteins.Nat. Genet. 2005; 37: 771-776Crossref PubMed Scopus (329) Google Scholar, Soukup et al., 2016Soukup S.F. Kuenen S. Vanhauwaert R. Manetsberger J. Hernández-Díaz S. Swerts J. Schoovaerts N. Vilain S. Gounko N.V. Vints K. et al.A LRRK2-Dependent EndophilinA Phosphoswitch Is Critical for Macroautophagy at Presynaptic Terminals.Neuron. 2016; 92: 829-844Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, Stavoe et al., 2016Stavoe A.K. Hill S.E. Hall D.H. Colón-Ramos D.A. KIF1A/UNC-104 Transports ATG-9 to Regulate Neurodevelopment and Autophagy at Synapses.Dev. Cell. 2016; 38: 171-185Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). This spatial specificity prompts a number of questions about the regulation of autophagy in neurons. What signals instruct autophagosome biogenesis at the synapse? How are different autophagic steps distributed and coordinated within distinct subcellular compartments of the neuron? How do the specialized environments of those compartments contribute to the regulation of autophagy? In addition to autophagy’s key roles in neuronal physiology, the spatial separation of the steps of autophagy in neurons affords the autophagy field an opportunity to rigorously examine the compartmentalized events of autophagosome biogenesis and degradation with a greater resolution than in non-neuronal cells. Concepts emerging from neurons regarding how cells compartmentalize and coordinate the different steps of autophagy across time and space will likely illuminate our understanding of the regulation of autophagy in other cell types. The first evidence for compartmentalized activity of autophagosomes came from electron micrographs of neurons which revealed the presence of double-membrane structures (which were later termed autophagosomes) in growing axon terminals (Bunge, 1973Bunge M.B. Fine structure of nerve fibers and growth cones of isolated sympathetic neurons in culture.J. Cell Biol. 1973; 56: 713-735Crossref PubMed Google Scholar). This study described cup-like isolation membranes in axons, consistent with biogenesis of autophagosomes. It also described fully formed, closed, double-membrane autophagosomes and electron-dense cargo-containing multilamellar structures that reflect autolysosomes arising from autophagosome and lysosome fusion in axons. While the electron microscopy data could not reveal the progression of individual structures over time, these studies did provide evidence that distinct steps of autophagy, ranging from biogenesis to autolysosome formation, occur in axon terminals. More recent studies have made use of translational fusions with fluorescent proteins to examine the dynamic progression of autophagy in neurons. The preferred markers for autophagosomes include yeast Atg8 and its orthologs, such as the LC3 and GABARAP families in mammals and zebrafish, Atg8 in Drosophila melanogaster, and LGG-1 and LGG-2 in C. elegans (Klionsky et al., 2012Klionsky D.J. Abdalla F.C. Abeliovich H. Abraham R.T. Acevedo-Arozena A. Adeli K. Agholme L. Agnello M. Agostinis P. Aguirre-Ghiso J.A. et al.Guidelines for the use and interpretation of assays for monitoring autophagy.Autophagy. 2012; 8: 445-544Crossref PubMed Scopus (2512) Google Scholar, Meléndez et al., 2003Meléndez A. Tallóczy Z. Seaman M. Eskelinen E.L. Hall D.H. Levine B. Autophagy genes are essential for dauer development and life-span extension in C. elegans.Science. 2003; 301: 1387-1391Crossref PubMed Scopus (904) Google Scholar, Zhang et al., 2015Zhang H. Chang J.T. Guo B. Hansen M. Jia K. Kovács A.L. Kumsta C. Lapierre L.R. Legouis R. Lin L. et al.Guidelines for monitoring autophagy in Caenorhabditis elegans.Autophagy. 2015; 11: 9-27PubMed Google Scholar). Atg8 orthologs are ubiquitin-like proteins that are anchored to autophagic membranes via a covalent bond between the last glycine in Atg8 and a phosphatidylethanolamine (PE) phospholipid in the autophagosome membrane. Since Atg8 orthologs localize to immature and mature autophagic structures, tracking Atg8 family proteins enables in vivo tracking of autophagosome biogenesis, transport, and maturation. Soukup et al., 2016Soukup S.F. Kuenen S. Vanhauwaert R. Manetsberger J. Hernández-Díaz S. Swerts J. Schoovaerts N. Vilain S. Gounko N.V. Vints K. et al.A LRRK2-Dependent EndophilinA Phosphoswitch Is Critical for Macroautophagy at Presynaptic Terminals.Neuron. 2016; 92: 829-844Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar bridged these strategies by examining presynaptic Drosophila neuromuscular junctions using correlative light and electron microscopy (CLEM). They also demonstrated that Atg8-containing structures correspond to autophagosomes forming near presynaptic sites (Soukup et al., 2016Soukup S.F. Kuenen S. Vanhauwaert R. Manetsberger J. Hernández-Díaz S. Swerts J. Schoovaerts N. Vilain S. Gounko N.V. Vints K. et al.A LRRK2-Dependent EndophilinA Phosphoswitch Is Critical for Macroautophagy at Presynaptic Terminals.Neuron. 2016; 92: 829-844Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). While autophagosomes can form in neuronal cell bodies (Lee et al., 2011Lee S. Sato Y. Nixon R.A. Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer’s-like axonal dystrophy.J. Neurosci. 2011; 31: 7817-7830Crossref PubMed Scopus (254) Google Scholar, Maday and Holzbaur, 2016Maday S. Holzbaur E.L. Compartment-Specific Regulation of Autophagy in Primary Neurons.J. Neurosci. 2016; 36: 5933-5945Crossref PubMed Scopus (105) Google Scholar), autophagosome formation in axons is independent from cell body input and occurs even in axons that have been severed from their cell bodies (Hernandez et al., 2012Hernandez D. Torres C.A. Setlik W. Cebrián C. Mosharov E.V. Tang G. Cheng H.C. Kholodilov N. Yarygina O. Burke R.E. et al.Regulation of presynaptic neurotransmission by macroautophagy.Neuron. 2012; 74: 277-284Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, Soukup et al., 2016Soukup S.F. Kuenen S. Vanhauwaert R. Manetsberger J. Hernández-Díaz S. Swerts J. Schoovaerts N. Vilain S. Gounko N.V. Vints K. et al.A LRRK2-Dependent EndophilinA Phosphoswitch Is Critical for Macroautophagy at Presynaptic Terminals.Neuron. 2016; 92: 829-844Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). We note that most of the studies on the dynamics of autophagy in neurons have been performed in invertebrate organisms or in cultured neuron systems, in which synapses could arguably be more prone to autophagy-dependent remodeling. It will be important to establish how the observed cell biology of autophagy in these systems compares to that of intact myelinated or aged brains of mammals. But together, these studies in cultured neurons and intact invertebrate systems demonstrate that axonal autophagosomes do not necessarily arise from autophagosomes formed in the cell body and trafficked into the axon and indicate that autophagosome biogenesis occurs in the axon. These studies demonstrate that autophagosome biogenesis is compartmentalized in neurons, occurring at axonal terminals and near presynaptic compartments (Maday et al., 2012Maday S. Wallace K.E. Holzbaur E.L. Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons.J. Cell Biol. 2012; 196: 407-417Crossref PubMed Scopus (312) Google Scholar, Soukup et al., 2016Soukup S.F. Kuenen S. Vanhauwaert R. Manetsberger J. Hernández-Díaz S. Swerts J. Schoovaerts N. Vilain S. Gounko N.V. Vints K. et al.A LRRK2-Dependent EndophilinA Phosphoswitch Is Critical for Macroautophagy at Presynaptic Terminals.Neuron. 2016; 92: 829-844Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, Stavoe et al., 2016Stavoe A.K. Hill S.E. Hall D.H. Colón-Ramos D.A. KIF1A/UNC-104 Transports ATG-9 to Regulate Neurodevelopment and Autophagy at Synapses.Dev. Cell. 2016; 38: 171-185Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). In non-neuronal cell types, starvation is a major trigger for autophagy, inducing non-specific degradation of cellular materials to provide nutrients for metabolic processes. In neurons, starvation and starvation-related pathways can also induce autophagy. For example, nutrient deprivation in primary cortical neurons leads to increased autophagy (Young et al., 2009Young J.E. Martinez R.A. La Spada A.R. Nutrient deprivation induces neuronal autophagy and implicates reduced insulin signaling in neuroprotective autophagy activation.J. Biol. Chem. 2009; 284: 2363-2373Crossref PubMed Scopus (77) Google Scholar). mTOR, a canonical regulator of starvation-induced autophagy in non-neuronal cells, can also induce autophagy in neurons. mTOR is a kinase that is activated during growth and suppressed during starvation to promote autophagy (Yang and Klionsky, 2010Yang Z. Klionsky D.J. Mammalian autophagy: core molecular machinery and signaling regulation.Curr. Opin. Cell Biol. 2010; 22: 124-131Crossref PubMed Scopus (1248) Google Scholar). In mouse brains, short-term fasting led to decreased mTOR levels and increased numbers of autophagosomes in neurons (Alirezaei et al., 2010Alirezaei M. Kemball C.C. Flynn C.T. Wood M.R. Whitton J.L. Kiosses W.B. Short-term fasting induces profound neuronal autophagy.Autophagy. 2010; 6: 702-710Crossref PubMed Scopus (129) Google Scholar). In dopaminergic axons from striatal brain slices, inhibition of mTOR by the drug Rapamycin resulted in an increased number of autophagosomes near synaptic terminals, as well as a decrease in synaptic vesicle numbers (Hernandez et al., 2012Hernandez D. Torres C.A. Setlik W. Cebrián C. Mosharov E.V. Tang G. Cheng H.C. Kholodilov N. Yarygina O. Burke R.E. et al.Regulation of presynaptic neurotransmission by macroautophagy.Neuron. 2012; 74: 277-284Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar). Rapamycin-induced autophagy also regulates synaptic growth (Shen and Ganetzky, 2009Shen W. Ganetzky B. Autophagy promotes synapse development in Drosophila.J. Cell Biol. 2009; 187: 71-79Crossref PubMed Scopus (149) Google Scholar) and axon elongation in cortical neurons (Ban et al., 2013Ban B.K. Jun M.H. Ryu H.H. Jang D.J. Ahmad S.T. Lee J.A. Autophagy negatively regulates early axon growth in cortical neurons.Mol. Cell. Biol. 2013; 33: 3907-3919Crossref PubMed Google Scholar), consistent with a role for mTOR in starvation-mediated induction of autophagy and autophagic regulation of physiological processes in neurons. It is important to note that while starvation can induce autophagy in neurons, autophagosome biogenesis can also occur in neurons in a constitutive manner. In cultured neurons, autophagosomes are observed to constitutively form in the distal neurite even in the absence of stimuli such as starvation (Maday and Holzbaur, 2016Maday S. Holzbaur E.L. Compartment-Specific Regulation of Autophagy in Primary Neurons.J. Neurosci. 2016; 36: 5933-5945Crossref PubMed Scopus (105) Google Scholar, Maday et al., 2012Maday S. Wallace K.E. Holzbaur E.L. Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons.J. Cell Biol. 2012; 196: 407-417Crossref PubMed Scopus (312) Google Scholar). In Drosophila neurons, basal levels of autophagy also occur regardless of starvation but neuronal autophagy increases upon starvation (Soukup et al., 2016Soukup S.F. Kuenen S. Vanhauwaert R. Manetsberger J. Hernández-Díaz S. Swerts J. Schoovaerts N. Vilain S. Gounko N.V. Vints K. et al.A LRRK2-Dependent EndophilinA Phosphoswitch Is Critical for Macroautophagy at Presynaptic Terminals.Neuron. 2016; 92: 829-844Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). In C. elegans neurons, autophagy occurs at a basal level but increases following stimuli known to trigger autophagy in non-neuronal cells, such as starvation or exposure to noxious temperatures (Hill et al., 2019Hill S.E. Kauffman K.J. Krout M. Richmond J.E. Melia T.J. Colon-Ramos D.A. Maturation and Clearance of Autophagosomes in Neurons Depends on a Specific Cysteine Protease Isoform, ATG-4.2.Dev. Cell. 2019; 49: 251-266Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar and unpublished data). Together, these studies indicate that while stimuli known to trigger autophagy in non-neuronal cells can enhance autophagy in neurons, likely there are other pathways that regulate the observed basal levels of neuronal autophagy. Neuronal activity impacts the levels of neuronal autophagy. Applying the glutamate analog N-methyl-D-aspartic acid (NMDA), an excitotoxin, increased autophagosome biogenesis (as revealed by increases in autophagy under Bafilomycin A conditions where degradation is inhibited) and increased the numbers of autophagosomes in axons (Katsumata et al., 2010Katsumata K. Nishiyama J. Inoue T. Mizushima N. Takeda J. Yuzaki M. Dynein- and activity-dependent retrograde transport of autophagosomes in neuronal axons.Autophagy. 2010; 6: 378-385Crossref PubMed Scopus (45) Google Scholar). Consistent with these findings, exposing tissue culture neurons to media with high levels of potassium chloride (which facilitates neuronal depolarization) caused an increase in autophagosomes at nerve terminals (Shehata et al., 2012Shehata M. Matsumura H. Okubo-Suzuki R. Ohkawa N. Inokuchi K. Neuronal stimulation induces autophagy in hippocampal neurons that is involved in AMPA receptor degradation after chemical long-term depression.J. Neurosci. 2012; 32: 10413-10422Crossref PubMed Scopus (138) Google Scholar, Wang et al., 2015Wang T. Martin S. Papadopulos A. Harper C.B. Mavlyutov T.A. Niranjan D. Glass N.R. Cooper-White J.J. Sibarita J.B. Choquet D. et al.Control of autophagosome axonal retrograde flux by presynaptic activity unveiled using botulinum neurotoxin type a.J. Neurosci. 2015; 35: 6179-6194Crossref PubMed Scopus (58) Google Scholar). In Drosophila, prolonged neuronal activity induced by activating a temperature-sensitive T
Referência(s)