Journal articles: 'Endolysosomal system'

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Morgan, Anthony J., Frances M. Platt, Emyr Lloyd-Evans, and Antony Galione. "Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease." Biochemical Journal 439, no. 3 (October 13, 2011): 349–78. http://dx.doi.org/10.1042/bj20110949.

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Endosomes, lysosomes and lysosome-related organelles are emerging as important Ca2+ storage cellular compartments with a central role in intracellular Ca2+ signalling. Endocytosis at the plasma membrane forms endosomal vesicles which mature to late endosomes and culminate in lysosomal biogenesis. During this process, acquisition of different ion channels and transporters progressively changes the endolysosomal luminal ionic environment (e.g. pH and Ca2+) to regulate enzyme activities, membrane fusion/fission and organellar ion fluxes, and defects in these can result in disease. In the present review we focus on the physiology of the inter-related transport mechanisms of Ca2+ and H+ across endolysosomal membranes. In particular, we discuss the role of the Ca2+-mobilizing messenger NAADP (nicotinic acid adenine dinucleotide phosphate) as a major regulator of Ca2+ release from endolysosomes, and the recent discovery of an endolysosomal channel family, the TPCs (two-pore channels), as its principal intracellular targets. Recent molecular studies of endolysosomal Ca2+ physiology and its regulation by NAADP-gated TPCs are providing exciting new insights into the mechanisms of Ca2+-signal initiation that control a wide range of cellular processes and play a role in disease. These developments underscore a new central role for the endolysosomal system in cellular Ca2+ regulation and signalling.

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Fang, Cheng, Ting Li, Ying Li, Guan Jie Xu, Qi Wen Deng, Ya Jie Chen, Yun Nan Hou, Hon Cheung Lee, and Yong Juan Zhao. "CD38 produces nicotinic acid adenosine dinucleotide phosphate in the lysosome." Journal of Biological Chemistry 293, no. 21 (April 9, 2018): 8151–60. http://dx.doi.org/10.1074/jbc.ra118.002113.

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Nicotinic acid adenosine dinucleotide phosphate (NAADP) is a Ca2+-mobilizing second messenger that regulates a wide range of biological activities. However, the mechanism of its biogenesis remains controversial. CD38 is the only enzyme known to catalyze NAADP synthesis from NADP and nicotinic acid. CD38-mediated catalysis requires an acidic pH, suggesting that NAADP may be produced in acidic endolysosomes, but this hypothesis is untested. In this study, using human cell lines, we specifically directed CD38 to the endolysosomal system and assessed cellular NAADP production. First, we found that nanobodies targeting various epitopes on the C-terminal domain of CD38 could bind to cell surface–localized CD38 and induce its endocytosis. We also found that CD38 internalization occurred via a clathrin-dependent pathway, delivered CD38 to the endolysosome, and elevated intracellular NAADP levels. We also created a CD38 variant for lysosome-specific expression, which not only withstood the degradative environment in the lysosome, but was also much more active than WT CD38 in elevating cellular NAADP levels. Supplementing CD38-expressing cells with nicotinic acid substantially increased cellular NAADP levels. These results demonstrate that endolysosomal CD38 can produce NAADP in human cells. They further suggest that CD38's compartmentalization to the lysosome may allow for its regulation via substrate access, rather than enzyme activation, thereby providing a reliable mechanism for regulating cellular NAADP production.

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Teixeira, Maxime, Razan Sheta, Walid Idi, and Abid Oueslati. "Alpha-Synuclein and the Endolysosomal System in Parkinson’s Disease: Guilty by Association." Biomolecules 11, no. 9 (September 9, 2021): 1333. http://dx.doi.org/10.3390/biom11091333.

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Abnormal accumulation of the protein α- synuclein (α-syn) into proteinaceous inclusions called Lewy bodies (LB) is the neuropathological hallmark of Parkinson’s disease (PD) and related disorders. Interestingly, a growing body of evidence suggests that LB are also composed of other cellular components such as cellular membrane fragments and vesicular structures, suggesting that dysfunction of the endolysosomal system might also play a role in LB formation and neuronal degeneration. Yet the link between α-syn aggregation and the endolysosomal system disruption is not fully elucidated. In this review, we discuss the potential interaction between α-syn and the endolysosomal system and its impact on PD pathogenesis. We propose that the accumulation of monomeric and aggregated α-syn disrupt vesicles trafficking, docking, and recycling, leading to the impairment of the endolysosomal system, notably the autophagy-lysosomal degradation pathway. Reciprocally, PD-linked mutations in key endosomal/lysosomal machinery genes (LRRK2, GBA, ATP13A2) also contribute to increasing α-syn aggregation and LB formation. Altogether, these observations suggest a potential synergistic role of α-syn and the endolysosomal system in PD pathogenesis and represent a viable target for the development of disease-modifying treatment for PD and related disorders.

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PILLAY, Ché S., Edith ELLIOTT, and Clive DENNISON. "Endolysosomal proteolysis and its regulation." Biochemical Journal 363, no. 3 (April 24, 2002): 417–29. http://dx.doi.org/10.1042/bj3630417.

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The endolysosomal system comprises a unique environment for proteolysis, which is regulated in a manner that apparently does not involve protease inhibitors. The system comprises a series of membrane-bound intracellular compartments, within which endocytosed material and redundant cellular components are hydrolysed. Endocytosed material tends to flow vectorially through the system, proceeding through the early endosome, the endosome carrier vesicle, the late endosome and the lysosome. Phagocytosis and autophagy provide alternative entry points into the system. Late endosomes, lysosome/late endosome hybrid organelles, phagosomes and autophagosomes are the principal sites for proteolysis. In each case, hydrolytic competence is due to components of the endolysosomal system, i.e. proteases, lysosome-associated membrane proteins, H+-ATPases and possibly cysteine transporters. The view is emerging that lysosomes are organelles for the storage of hydrolases, perhaps in an inactivated form. Once a substrate has entered a proteolytically competent environment, the rate-limiting proteolytic steps are probably effected by cysteine endoproteinases. As these are affected by pH and possibly redox potential, they may be regulated by the organelle luminal environment. Regulation is probably also affected, among other factors, by organelle fusion reactions, whereby the meeting of enzyme and substrate may be controlled. Such systems would permit simultaneous regulation of a number of unrelated hydrolases.

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Bonifacino, Juan S., and Jacques Neefjes. "Moving and positioning the endolysosomal system." Current Opinion in Cell Biology 47 (August 2017): 1–8. http://dx.doi.org/10.1016/j.ceb.2017.01.008.

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Erb, Madalynn L., and Darren J. Moore. "LRRK2 and the Endolysosomal System in Parkinson’s Disease." Journal of Parkinson's Disease 10, no. 4 (October 27, 2020): 1271–91. http://dx.doi.org/10.3233/jpd-202138.

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Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant familial Parkinson’s disease (PD), with pathogenic mutations enhancing LRRK2 kinase activity. There is a growing body of evidence indicating that LRRK2 contributes to neuronal damage and pathology both in familial and sporadic PD, making it of particular interest for understanding the molecular pathways that underlie PD. Although LRRK2 has been extensively studied to date, our understanding of the seemingly diverse functions of LRRK2 throughout the cell remains incomplete. In this review, we discuss the functions of LRRK2 within the endolysosomal pathway. Endocytosis, vesicle trafficking pathways, and lysosomal degradation are commonly disrupted in many neurodegenerative diseases, including PD. Additionally, many PD-linked gene products function in these intersecting pathways, suggesting an important role for the endolysosomal system in maintaining protein homeostasis and neuronal health in PD. LRRK2 activity can regulate synaptic vesicle endocytosis, lysosomal function, Golgi network maintenance and sorting, vesicular trafficking and autophagy, with alterations in LRRK2 kinase activity serving to disrupt or regulate these pathways depending on the distinct cell type or model system. LRRK2 is critically regulated by at least two proteins in the endolysosomal pathway, Rab29 and VPS35, which may serve as master regulators of LRRK2 kinase activity. Investigating the function and regulation of LRRK2 in the endolysosomal pathway in diverse PD models, especially in vivo models, will provide critical insight into the cellular and molecular pathophysiological mechanisms driving PD and whether LRRK2 represents a viable drug target for disease-modification in familial and sporadic PD.

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Klumperman, J., and G. Raposo. "The Complex Ultrastructure of the Endolysosomal System." Cold Spring Harbor Perspectives in Biology 6, no. 10 (May 22, 2014): a016857. http://dx.doi.org/10.1101/cshperspect.a016857.

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Lloyd-Evans, Emyr, Helen Waller-Evans, Ksenia Peterneva, and Frances M. Platt. "Endolysosomal calcium regulation and disease." Biochemical Society Transactions 38, no. 6 (November 24, 2010): 1458–64. http://dx.doi.org/10.1042/bst0381458.

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Until recently, the mechanisms that regulate endolysosomal calcium homoeostasis were poorly understood. The discovery of the molecular target of NAADP (nicotinic acid–adenine dinucleotide phosphate) as the two-pore channels resident in the endolysosomal system has highlighted this compartment as an important calcium store. The recent findings that dysfunctional NAADP release leads to defective endocytic function which in turn results in secondary lipid accumulation in the lysosomal storage disease Niemann–Pick type C, is the first evidence of a direct connection between a human disease and defective lysosomal calcium release. In the present review, we provide a summary of the current knowledge on mechanisms of calcium homoeostasis within the endolysosomal system and how these mechanisms may be affected in human metabolic disorders.

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Toupenet Marchesi, Liriopé, Marion Leblanc, and Giovanni Stevanin. "Current Knowledge of Endolysosomal and Autophagy Defects in Hereditary Spastic Paraplegia." Cells 10, no. 7 (July 2, 2021): 1678. http://dx.doi.org/10.3390/cells10071678.

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Hereditary spastic paraplegia (HSP) refers to a group of neurological disorders involving the degeneration of motor neurons. Due to their clinical and genetic heterogeneity, finding common effective therapeutics is difficult. Therefore, a better understanding of the common pathological mechanisms is necessary. The role of several HSP genes/proteins is linked to the endolysosomal and autophagic pathways, suggesting a functional convergence. Furthermore, impairment of these pathways is particularly interesting since it has been linked to other neurodegenerative diseases, which would suggest that the nervous system is particularly sensitive to the disruption of the endolysosomal and autophagic systems. In this review, we will summarize the involvement of HSP proteins in the endolysosomal and autophagic pathways in order to clarify their functioning and decipher some of the pathological mechanisms leading to HSP.

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Gao, Song, Aaron E. Casey, Tim J. Sargeant, and Ville-Petteri Mäkinen. "Genetic variation within endolysosomal system is associated with late-onset Alzheimer’s disease." Brain 141, no. 9 (August 16, 2018): 2711–20. http://dx.doi.org/10.1093/brain/awy197.

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AbstractLate-onset Alzheimer’s disease is the most common dementia type, yet no treatment exists to stop the neurodegeneration. Evidence from monogenic lysosomal diseases, neuronal pathology and experimental models suggest that autophagic and endolysosomal dysfunction may contribute to neurodegeneration by disrupting the degradation of potentially neurotoxic molecules such as amyloid-β and tau. However, it is uncertain how well the evidence from rare disorders and experimental models capture causal processes in common forms of dementia, including late-onset Alzheimer’s disease. For this reason, we set out to investigate if autophagic and endolysosomal genes were enriched for genetic variants that convey increased risk of Alzheimer’s disease; such a finding would provide population-based support for the endolysosomal hypothesis of neurodegeneration. We quantified the collective genetic associations between the endolysosomal system and Alzheimer’s disease in three genome-wide associations studies (combined n = 62 415). We used the Mergeomics pathway enrichment algorithm that incorporates permutations of the full hierarchical cascade of SNP-gene-pathway to estimate enrichment. We used a previously published collection of 891 autophagic and endolysosomal genes (denoted as AphagEndoLyso, and derived from the Lysoplex sequencing platform) as a proxy for cellular processes related to autophagy, endocytosis and lysosomal function. We also investigated a subset of 142 genes of the 891 that have been implicated in Mendelian diseases (MenDisLyso). We found that both gene sets were enriched for genetic Alzheimer’s associations: an enrichment score 3.67 standard deviations from the null model (P = 0.00012) was detected for AphagEndoLyso, and a score 3.36 standard deviations from the null model (P = 0.00039) was detected for MenDisLyso. The high enrichment score was specific to the AphagEndoLyso gene set (stronger than 99.7% of other tested pathways) and to Alzheimer’s disease (stronger than all other tested diseases). The APOE locus explained most of the MenDisLyso signal (1.16 standard deviations after APOE removal, P = 0.12), but the AphagEndoLyso signal was less affected (3.35 standard deviations after APOE removal, P = 0.00040). Additional sensitivity analyses further indicated that the AphagEndoLyso Gene Set contained an aggregate genetic association that comprised a combination of subtle genetic signals in multiple genes. We also observed an enrichment of Parkinson’s disease signals for MenDisLyso (3.25 standard deviations) and for AphagEndoLyso (3.95 standard deviations from the null model), and a brain-specific pattern of gene expression for AphagEndoLyso in the Gene Tissue Expression Project dataset. These results provide evidence that a diffuse aggregation of genetic perturbations to the autophagy and endolysosomal system may mediate late-onset Alzheimer’s risk in human populations.

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Vidyadhara, D. J., John E. Lee, and Sreeganga S. Chandra. "Role of the endolysosomal system in Parkinson’s disease." Journal of Neurochemistry 150, no. 5 (July 31, 2019): 487–506. http://dx.doi.org/10.1111/jnc.14820.

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Repnik, U., M. H. Cesen, and B. Turk. "The Endolysosomal System in Cell Death and Survival." Cold Spring Harbor Perspectives in Biology 5, no. 1 (January 1, 2013): a008755. http://dx.doi.org/10.1101/cshperspect.a008755.

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Rawet-Slobodkin, Moran, and Zvulun Elazar. "PLEKHM1: A Multiprotein Adaptor for the Endolysosomal System." Molecular Cell 57, no. 1 (January 2015): 1–3. http://dx.doi.org/10.1016/j.molcel.2014.12.022.

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Wallroth, Alexander, and Volker Haucke. "Phosphoinositide conversion in endocytosis and the endolysosomal system." Journal of Biological Chemistry 293, no. 5 (December 27, 2017): 1526–35. http://dx.doi.org/10.1074/jbc.r117.000629.

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Dong, Xiaonan, Adam Cheng, Zhongju Zou, Yih-Sheng Yang, Rhea M. Sumpter, Chou-Long Huang, Govind Bhagat, Herbert W. Virgin, Sergio A. Lira, and Beth Levine. "Endolysosomal trafficking of viral G protein-coupled receptor functions in innate immunity and control of viral oncogenesis." Proceedings of the National Academy of Sciences 113, no. 11 (February 29, 2016): 2994–99. http://dx.doi.org/10.1073/pnas.1601860113.

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The ubiquitin-proteasome system degrades viral oncoproteins and other microbial virulence factors; however, the role of endolysosomal degradation pathways in these processes is unclear. Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma, and a constitutively active viral G protein-coupled receptor (vGPCR) contributes to the pathogenesis of KSHV-induced tumors. We report that a recently discovered autophagy-related protein, Beclin 2, interacts with KSHV GPCR, facilitates its endolysosomal degradation, and inhibits vGPCR-driven oncogenic signaling. Furthermore, monoallelic loss of Becn2 in mice accelerates the progression of vGPCR-induced lesions that resemble human Kaposi’s sarcoma. Taken together, these findings indicate that Beclin 2 is a host antiviral molecule that protects against the pathogenic effects of KSHV GPCR by facilitating its endolysosomal degradation. More broadly, our data suggest a role for host endolysosomal trafficking pathways in regulating viral pathogenesis and oncogenic signaling.

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Cesar-Silva, Daniella, Filipe S. Pereira-Dutra, Ana Lucia Moraes Moraes Giannini, and Cecília Jacques G. Jacques G. de Almeida. "The Endolysosomal System: The Acid Test for SARS-CoV-2." International Journal of Molecular Sciences 23, no. 9 (April 20, 2022): 4576. http://dx.doi.org/10.3390/ijms23094576.

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This review aims to describe and discuss the different functions of the endolysosomal system, from homeostasis to its vital role during viral infections. We will initially describe endolysosomal system’s main functions, presenting recent data on how its compartments are essential for host defense to explore later how SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) and other coronaviruses subvert these organelles for their benefit. It is clear that to succeed, pathogens’ evolution favored the establishment of ways to avoid, escape, or manipulate lysosomal function. The unavoidable coexistence with such an unfriendly milieu imposed on viruses the establishment of a vast array of strategies to make the most out of the invaded cell’s machinery to produce new viruses and maneuvers to escape the host’s defense system.

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Litvinov, Ilia K., Tatiana N. Belyaeva, Anna V. Salova, Nikolay D. Aksenov, Pavel S. Chelushkin, Anastasia I. Solomatina, Sergey P. Tunik, and Elena S. Kornilova. "The Dual Luminescence Lifetime pH/Oxygen Sensor: Evaluation of Applicability for Intravital Analysis of 2D- and 3D-Cultivated Human Endometrial Mesenchymal Stromal Cells." International Journal of Molecular Sciences 24, no. 21 (October 26, 2023): 15606. http://dx.doi.org/10.3390/ijms242115606.

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The oxygenation of cells and tissues and acidification of the cellular endolysosomal system are among the major factors that ensure normal functioning of an organism and are violated in various pathologies. Recording of these parameters and their changes under various conditions is an important task for both basic research and clinical applications. In the present work, we utilized internalizable dual pH/O2 lifetime sensor (Ir-HSA-FITC) based on the covalent conjugation of human serum albumin (HSA) with fluorescein isothiocyanate (FITC) as pH sensor and an orthometalated iridium complex as O2 sensor. The probe was tested for simultaneous detection of acidification level and oxygen concentration in endolysosomes of endometrial mesenchymal stem/stromal cells (enMSCs) cultivated as 2D monolayers and 3D spheroids. Using a combined FLIM/PLIM approach, we found that due to high autofluorescence of enMSCs FITC lifetime signal in control cells was insufficient to estimate pH changes. However, using flow cytometry and confocal microscopy, we managed to detect the FITC signal response to inhibition of endolysosomal acidification by Bafilomycin A1. The iridium chromophore phosphorescence was detected reliably by all methods used. It was demonstrated that the sensor, accumulated in endolysosomes for 24 h, disappeared from proliferating 2D enMSCs by 72 h, but can still be recorded in non-proliferating spheroids. PLIM showed high sensitivity and responsiveness of iridium chromophore phosphorescence to experimental hypoxia both in 2D and 3D cultures. In spheroids, the phosphorescence signal was detected at a depth of up to 60 μm using PLIM and showed a gradient in the intracellular O2 level towards their center.

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Infarinato, Nicole. "Mahak Sharma: Weaving through traffic." Journal of Cell Biology 218, no. 3 (February 19, 2019): 725–26. http://dx.doi.org/10.1083/jcb.201902008.

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Kucera, Ana, Oddmund Bakke, and Cinzia Progida. "The multiple roles of Rab9 in the endolysosomal system." Communicative & Integrative Biology 9, no. 4 (July 3, 2016): e1204498. http://dx.doi.org/10.1080/19420889.2016.1204498.

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Winckler, Bettina, Victor Faundez, Sandra Maday, Qian Cai, Cláudia Guimas Almeida, and Huaye Zhang. "The Endolysosomal System and Proteostasis: From Development to Degeneration." Journal of Neuroscience 38, no. 44 (October 31, 2018): 9364–74. http://dx.doi.org/10.1523/jneurosci.1665-18.2018.

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Wang, Haibin, Wen-Ting Lo, and Volker Haucke. "Phosphoinositide switches in endocytosis and in the endolysosomal system." Current Opinion in Cell Biology 59 (August 2019): 50–57. http://dx.doi.org/10.1016/j.ceb.2019.03.011.

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Bécot, Anaïs, Charlotte Volgers, and Guillaume van Niel. "Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation." Biomedicines 8, no. 8 (August 4, 2020): 272. http://dx.doi.org/10.3390/biomedicines8080272.

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In Alzheimer′s disease (AD), endolysosomal dysfunctions are amongst the earliest cellular features to appear. Each organelle of the endolysosomal system, from the multivesicular body (MVB) to the lysosome, contributes to the homeostasis of amyloid precursor protein (APP) cleavage products including β-amyloid (Aβ) peptides. Hence, this review will attempt to disentangle how changes in the endolysosomal system cumulate to the generation of toxic amyloid species and hamper their degradation. We highlight that the formation of MVBs and the generation of amyloid species are closely linked and describe how the molecular machineries acting at MVBs determine the generation and sorting of APP cleavage products towards their degradation or release in association with exosomes. In particular, we will focus on AD-related distortions of the endolysomal system that divert it from its degradative function to favour the release of exosomes and associated amyloid species. We propose here that such an imbalance transposed at the brain scale poses a novel concept of transmissible endosomal intoxication (TEI). This TEI would initiate a self-perpetuating transmission of endosomal dysfunction between cells that would support the propagation of amyloid species in neurodegenerative diseases.

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Chen, Yu, David C. Gershlick, Sang Yoon Park, and Juan S. Bonifacino. "Segregation in the Golgi complex precedes export of endolysosomal proteins in distinct transport carriers." Journal of Cell Biology 216, no. 12 (October 4, 2017): 4141–51. http://dx.doi.org/10.1083/jcb.201707172.

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Biosynthetic sorting of newly synthesized transmembrane cargos to endosomes and lysosomes is thought to occur at the TGN through recognition of sorting signals in the cytosolic tails of the cargos by adaptor proteins, leading to cargo packaging into coated vesicles destined for the endolysosomal system. Here we present evidence for a different mechanism in which two sets of endolysosomal proteins undergo early segregation to distinct domains of the Golgi complex by virtue of the proteins’ luminal and transmembrane domains. Proteins in one Golgi domain exit into predominantly vesicular carriers by interaction of sorting signals with adaptor proteins, but proteins in the other domain exit into predominantly tubular carriers shared with plasma membrane proteins, independently of signal–adaptor interactions. These findings demonstrate that sorting of endolysosomal proteins begins at an earlier stage and involves mechanisms that partly differ from those described by classical models.

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Prat Castro, Sandra, Veronika Kudrina, Dawid Jaślan, Julia Böck, Anna Scotto Rosato, and Christian Grimm. "Neurodegenerative Lysosomal Storage Disorders: TPC2 Comes to the Rescue!" Cells 11, no. 18 (September 8, 2022): 2807. http://dx.doi.org/10.3390/cells11182807.

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Lysosomal storage diseases (LSDs) resulting from inherited gene mutations constitute a family of disorders that disturb lysosomal degradative function leading to abnormal storage of macromolecular substrates. In most LSDs, central nervous system (CNS) involvement is common and leads to the progressive appearance of neurodegeneration and early death. A growing amount of evidence suggests that ion channels in the endolysosomal system play a crucial role in the pathology of neurodegenerative LSDs. One of the main basic mechanisms through which the endolysosomal ion channels regulate the function of the endolysosomal system is Ca2+ release, which is thought to be essential for intracellular compartment fusion, fission, trafficking and lysosomal exocytosis. The intracellular TRPML (transient receptor potential mucolipin) and TPC (two-pore channel) ion channel families constitute the main essential Ca2+-permeable channels expressed on endolysosomal membranes, and they are considered potential drug targets for the prevention and treatment of LSDs. Although TRPML1 activation has shown rescue effects on LSD phenotypes, its activity is pH dependent, and it is blocked by sphingomyelin accumulation, which is characteristic of some LSDs. In contrast, TPC2 activation is pH-independent and not blocked by sphingomyelin, potentially representing an advantage over TRPML1. Here, we discuss the rescue of cellular phenotypes associated with LSDs such as cholesterol and lactosylceramide (LacCer) accumulation or ultrastructural changes seen by electron microscopy, mediated by the small molecule agonist of TPC2, TPC2-A1-P, which promotes lysosomal exocytosis and autophagy. In summary, new data suggest that TPC2 is a promising target for the treatment of different types of LSDs such as MLIV, NPC1, and Batten disease, both in vitro and in vivo.

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Núñez, MarcoT, DanielA Borquez, and PamelaJ Urrutia. "Iron, the endolysosomal system and neuroinflammation: a matter of balance." Neural Regeneration Research 17, no. 5 (2022): 1003. http://dx.doi.org/10.4103/1673-5374.324847.

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Hayashi, Hideki, Ting Wang, Masayuki Tanaka, Sanae Ogiwara, Chisa Okada, Masatoshi Ito, Nahoko Fukunishi, et al. "Monitoring the autophagy-endolysosomal system using monomeric Keima-fused MAP1LC3B." PLOS ONE 15, no. 6 (June 8, 2020): e0234180. http://dx.doi.org/10.1371/journal.pone.0234180.

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Xu, Ying, Hui-Yi Zhang, Ye Tian, Han-Yan Shi, and Ya Cai. "The critical role of the endolysosomal system in cerebral ischemia." Neural Regeneration Research 18, no. 5 (2023): 983. http://dx.doi.org/10.4103/1673-5374.355745.

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Delevoye, Cédric, Michael S. Marks, and Graça Raposo. "Lysosome-related organelles as functional adaptations of the endolysosomal system." Current Opinion in Cell Biology 59 (August 2019): 147–58. http://dx.doi.org/10.1016/j.ceb.2019.05.003.

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Galione, Antony, Anthony J. Morgan, Abdelilah Arredouani, Lianne C. Davis, Katja Rietdorf, Margarida Ruas, and John Parrington. "NAADP as an intracellular messenger regulating lysosomal calcium-release channels." Biochemical Society Transactions 38, no. 6 (November 24, 2010): 1424–31. http://dx.doi.org/10.1042/bst0381424.

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Recent studies into the mechanisms of action of the Ca2+-mobilizing messenger NAADP (nicotinic acid–adenine dinucleotide phosphate) have demonstrated that a novel family of intracellular Ca2+-release channels termed TPCs (two-pore channels) are components of the NAADP receptor. TPCs appear to be exclusively localized to the endolysosomal system. These findings confirm previous pharmacological and biochemical studies suggesting that NAADP targets acidic Ca2+ stores rather than the endoplasmic reticulum, the major site of action of the other two principal Ca2+-mobilizing messengers, InsP3 and cADPR (cADP-ribose). Studies of the messenger roles of NAADP and the function of TPCs highlight the novel role of lysosomes and other organelles of the endocytic pathway as messenger-regulated Ca2+ stores which also affects the regulation of the endolysosomal system.

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Patel, Sandip, and Eugen Brailoiu. "Triggering of Ca2+ signals by NAADP-gated two-pore channels: a role for membrane contact sites?" Biochemical Society Transactions 40, no. 1 (January 19, 2012): 153–57. http://dx.doi.org/10.1042/bst20110693.

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NAADP (nicotinic acid–adenine dinucleotide phosphate) is a potent Ca2+-mobilizing messenger implicated in many Ca2+-dependent cellular processes. It is highly unusual in that it appears to trigger Ca2+ release from acidic organelles such as lysosomes. These signals are often amplified by archetypal Ca2+ channels located in the endoplasmic reticulum. Recent studies have converged on the TPCs (two-pore channels) which localize to the endolysosomal system as the likely primary targets through which NAADP mediates its effects. ‘Chatter’ between TPCs and endoplasmic reticulum Ca2+ channels is disrupted when TPCs are directed away from the endolysosomal system. This suggests that intracellular Ca2+ release channels may be closely apposed, possibly at specific membrane contact sites between acidic organelles and the endoplasmic reticulum.

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Manzoni, Claudia. "The LRRK2–macroautophagy axis and its relevance to Parkinson's disease." Biochemical Society Transactions 45, no. 1 (February 8, 2017): 155–62. http://dx.doi.org/10.1042/bst20160265.

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A wide variety of different functions and an impressive array of interactors have been associated with leucine-rich repeat kinase 2 (LRRK2) over the years. Here, I discuss the hypothesis that LRRK2 may be capable of interacting with different proteins at different times and places, therefore, controlling a plethora of diverse functions based on the different complexes formed. Among these, I will then focus on macroautophagy in the general context of the endolysosomal system. First, the relevance of autophagy in Parkinson's disease will be evaluated giving a brief overview of all the relevant Parkinson's disease genes; then, the association of LRRK2 with macroautophagy and the endolysosomal pathway will be analyzed based on the supporting literature.

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Carlin, Cathleen, and Danny Manor. "Adenovirus Reveals New Pathway for Cholesterol Egress from the Endolysosomal System." International Journal of Molecular Sciences 21, no. 16 (August 13, 2020): 5808. http://dx.doi.org/10.3390/ijms21165808.

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In addition to providing invaluable insights to the host response to viral infection, adenovirus continues to be an important model system for discovering basic aspects of cell biology. This is especially true for products of early region three (E3), which have provided the foundation for understanding many new mechanisms regulating intracellular trafficking of host cell proteins involved in the host immune response. Cholesterol homeostasis is vital for proper cellular physiology, and disturbances in cholesterol balance are increasingly recognized as important factors in human disease. Despite its central role in numerous aspects of cellular functions, the mechanisms responsible for delivery of dietary cholesterol to the endoplasmic reticulum, where the lipid metabolic and regulatory machinery reside, remain poorly understood. In this review, we describe a novel intracellular pathway for cholesterol trafficking that has been co-opted by an adenovirus E3 gene product. We describe what is known about the molecular regulation of this pathway, how it might benefit viral replication, and its potential involvement in normal cell physiology. Finally, we make a case that adenovirus has co-opted a cellular pathway that may be dysregulated in various human diseases.

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Song, Lin, Ramesh Rijal, Malte Karow, Maria Stumpf, Oliver Hahn, Laura Park, Robert Insall, et al. "Expression of N471D strumpellin leads to defects in the endolysosomal system." Disease Models & Mechanisms 11, no. 9 (July 30, 2018): dmm033449. http://dx.doi.org/10.1242/dmm.033449.

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Dosil, Sara G., Amelia Rojas-Gomez, Francisco Sánchez-Madrid, and Noa B. Martín-Cófreces. "The Swing of Lipids at Peroxisomes and Endolysosomes in T Cell Activation." International Journal of Molecular Sciences 21, no. 8 (April 19, 2020): 2859. http://dx.doi.org/10.3390/ijms21082859.

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The immune synapse (IS) is a well-known intercellular communication platform, organized at the interphase between the antigen presenting cell (APC) and the T cell. After T cell receptor (TCR) stimulation, signaling from plasma membrane proteins and lipids is amplified by molecules and downstream pathways for full synapse formation and maintenance. This secondary signaling event relies on intracellular reorganization at the IS, involving the cytoskeleton and components of the secretory/recycling machinery, such as the Golgi apparatus and the endolysosomal system (ELS). T cell activation triggers a metabolic reprogramming that involves the synthesis of lipids, which act as signaling mediators, and an increase of mitochondrial activity. Then, this mitochondrial activity results in elevated reactive oxygen species (ROS) production that may lead to cytotoxicity. The regulation of ROS levels requires the concerted action of mitochondria and peroxisomes. In this review, we analyze this reprogramming and the signaling implications of endolysosomal, mitochondrial, peroxisomal, and lipidic systems in T cell activation.

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Ivanova, Daniela, Katharine L. Dobson, Akshada Gajbhiye, Elizabeth C. Davenport, Daniela Hacker, Sila K. Ultanir, Matthias Trost, and Michael A. Cousin. "Control of synaptic vesicle release probability via VAMP4 targeting to endolysosomes." Science Advances 7, no. 18 (April 2021): eabf3873. http://dx.doi.org/10.1126/sciadv.abf3873.

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Synaptic vesicle (SV) release probability (Pr), determines the steady state and plastic control of neurotransmitter release. However, how diversity in SV composition arises and regulates the Pr of individual SVs is not understood. We found that modulation of the copy number of the noncanonical vesicular SNARE (soluble N-ethylmaleimide–sensitive factor attachment protein receptor), vesicle-associated membrane protein 4 (VAMP4), on SVs is key for regulating Pr. Mechanistically, this is underpinned by its reduced ability to form an efficient SNARE complex with canonical plasma membrane SNAREs. VAMP4 has unusually high synaptic turnover and is selectively sorted to endolysosomes during activity-dependent bulk endocytosis. Disruption of endolysosomal trafficking and function markedly increased the abundance of VAMP4 in the SV pool and inhibited SV fusion. Together, our results unravel a new mechanism for generating SV heterogeneity and control of Pr through coupling of SV recycling to a major clearing system that regulates protein homeostasis.

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Delgado, Jose M., Logan Wallace Shepard, Sarah W. Lamson, Samantha L. Liu, and Christopher J. Shoemaker. "The ER membrane protein complex restricts mitophagy by controlling BNIP3 turnover." EMBO Journal 43, no. 1 (December 15, 2023): 32–60. http://dx.doi.org/10.1038/s44318-023-00006-z.

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AbstractLysosomal degradation of autophagy receptors is a common proxy for selective autophagy. However, we find that two established mitophagy receptors, BNIP3 and BNIP3L/NIX, are constitutively delivered to lysosomes in an autophagy-independent manner. This alternative lysosomal delivery of BNIP3 accounts for nearly all its lysosome-mediated degradation, even upon mitophagy induction. To identify how BNIP3, a tail-anchored protein in the outer mitochondrial membrane, is delivered to lysosomes, we performed a genome-wide CRISPR screen for factors influencing BNIP3 flux. This screen revealed both known modifiers of BNIP3 stability as well as a pronounced reliance on endolysosomal components, including the ER membrane protein complex (EMC). Importantly, the endolysosomal system and the ubiquitin–proteosome system regulated BNIP3 independently. Perturbation of either mechanism is sufficient to modulate BNIP3-associated mitophagy and affect underlying cellular physiology. More broadly, these findings extend recent models for tail-anchored protein quality control and install endosomal trafficking and lysosomal degradation in the canon of pathways that tightly regulate endogenous tail-anchored protein localization.

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McLelland, Gian-Luca, Sydney A. Lee, Heidi M. McBride, and Edward A. Fon. "Syntaxin-17 delivers PINK1/parkin-dependent mitochondrial vesicles to the endolysosomal system." Journal of Cell Biology 214, no. 3 (July 25, 2016): 275–91. http://dx.doi.org/10.1083/jcb.201603105.

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Mitochondria are considered autonomous organelles, physically separated from endocytic and biosynthetic pathways. However, recent work uncovered a PINK1/parkin-dependent vesicle transport pathway wherein oxidized or damaged mitochondrial content are selectively delivered to the late endosome/lysosome for degradation, providing evidence that mitochondria are indeed integrated within the endomembrane system. Given that mitochondria have not been shown to use canonical soluble NSF attachment protein receptor (SNARE) machinery for fusion, the mechanism by which mitochondrial-derived vesicles (MDVs) are targeted to the endosomal compartment has remained unclear. In this study, we identify syntaxin-17 as a core mitochondrial SNARE required for the delivery of stress-induced PINK1/parkin-dependent MDVs to the late endosome/lysosome. Syntaxin-17 remains associated with mature MDVs and forms a ternary SNARE complex with SNAP29 and VAMP7 to mediate MDV–endolysosome fusion in a manner dependent on the homotypic fusion and vacuole protein sorting (HOPS) tethering complex. Syntaxin-17 can be traced to the last eukaryotic common ancestor, hinting that the removal of damaged mitochondrial content may represent one of the earliest vesicle transport routes in the cell.

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Zeigerer, Anja, Jerome Gilleron, Roman L. Bogorad, Giovanni Marsico, Hidenori Nonaka, Sarah Seifert, Hila Epstein-Barash, et al. "Rab5 is necessary for the biogenesis of the endolysosomal system in vivo." Nature 485, no. 7399 (May 2012): 465–70. http://dx.doi.org/10.1038/nature11133.

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Drecktrah, Dan, Leigh A. Knodler, Dale Howe, and Olivia Steele-Mortimer. "Salmonella Trafficking is Defined by Continuous Dynamic Interactions with the Endolysosomal System." Traffic 8, no. 3 (December 21, 2006): 212–25. http://dx.doi.org/10.1111/j.1600-0854.2006.00529.x.

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Yu, Yue, Dongsheng Chen, Stephen M. Farmer, Shiyu Xu, Beatriz Rios, Amanda Solbach, Xin Ye, Lili Ye, and Sheng Zhang. "Endolysosomal trafficking controls yolk granule biogenesis in vitellogenic Drosophila oocytes." PLOS Genetics 20, no. 2 (February 5, 2024): e1011152. http://dx.doi.org/10.1371/journal.pgen.1011152.

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Endocytosis and endolysosomal trafficking are essential for almost all aspects of physiological functions of eukaryotic cells. As our understanding on these membrane trafficking events are mostly from studies in yeast and cultured mammalian cells, one challenge is to systematically evaluate the findings from these cell-based studies in multicellular organisms under physiological settings. One potentially valuable in vivo system to address this challenge is the vitellogenic oocyte in Drosophila, which undergoes extensive endocytosis by Yolkless (Yl), a low-density lipoprotein receptor (LDLR), to uptake extracellular lipoproteins into oocytes and package them into a specialized lysosome, the yolk granule, for storage and usage during later development. However, by now there is still a lack of sufficient understanding on the molecular and cellular processes that control yolk granule biogenesis. Here, by creating genome-tagging lines for Yl receptor and analyzing its distribution in vitellogenic oocytes, we observed a close association of different endosomal structures with distinct phosphoinositides and actin cytoskeleton dynamics. We further showed that Rab5 and Rab11, but surprisingly not Rab4 and Rab7, are essential for yolk granules biogenesis. Instead, we uncovered evidence for a potential role of Rab7 in actin regulation and observed a notable overlap of Rab4 and Rab7, two Rab GTPases that have long been proposed to have distinct spatial distribution and functional roles during endolysosomal trafficking. Through a small-scale RNA interference (RNAi) screen on a set of reported Rab5 effectors, we showed that yolk granule biogenesis largely follows the canonical endolysosomal trafficking and maturation processes. Further, the data suggest that the RAVE/V-ATPase complexes function upstream of or in parallel with Rab7, and are involved in earlier stages of endosomal trafficking events. Together, our study provides s novel insights into endolysosomal pathways and establishes vitellogenic oocyte in Drosophila as an excellent in vivo model for dissecting the highly complex membrane trafficking events in metazoan.

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Komori, Tadayuki, and Tomoki Kuwahara. "An Update on the Interplay between LRRK2, Rab GTPases and Parkinson’s Disease." Biomolecules 13, no. 11 (November 13, 2023): 1645. http://dx.doi.org/10.3390/biom13111645.

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Over the last decades, research on the pathobiology of neurodegenerative diseases has greatly evolved, revealing potential targets and mechanisms linked to their pathogenesis. Parkinson’s disease (PD) is no exception, and recent studies point to the involvement of endolysosomal defects in PD. The endolysosomal system, which tightly controls a flow of endocytosed vesicles targeted either for degradation or recycling, is regulated by a number of Rab GTPases. Their associations with leucine-rich repeat kinase 2 (LRRK2), a major causative and risk protein of PD, has also been one of the hot topics in the field. Understanding their interactions and functions is critical for unraveling their contribution to PD pathogenesis. In this review, we summarize recent studies on LRRK2 and Rab GTPases and attempt to provide more insight into the interaction of LRRK2 with each Rab and its relationship to PD.

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Gengyo-Ando, Keiko, Eriko Kage-Nakadai, Sawako Yoshina, Muneyoshi Otori, Yuko Kagawa-Nagamura, Junichi Nakai, and Shohei Mitani. "Distinct roles of the two VPS33 proteins in the endolysosomal system inCaenorhabditis elegans." Traffic 17, no. 11 (October 3, 2016): 1197–213. http://dx.doi.org/10.1111/tra.12430.

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SINHA, D., M. VALAPALA, JS ZIGLER, and S. HOSE. "The endolysosomal system and AMD: Insights from a novel genetically engineered mouse model." Acta Ophthalmologica 91 (August 2013): 0. http://dx.doi.org/10.1111/j.1755-3768.2013.2271.x.

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Perrin, Priscillia, Marlieke LM Jongsma, Jacques Neefjes, and Ilana Berlin. "The labyrinth unfolds: architectural rearrangements of the endolysosomal system in antigen-presenting cells." Current Opinion in Immunology 58 (June 2019): 1–8. http://dx.doi.org/10.1016/j.coi.2018.12.004.

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Yonamine, Ikuko, Takeshi Bamba, Niraj K. Nirala, Nahid Jesmin, Teresa Kosakowska-Cholody, Kunio Nagashima, Eiichiro Fukusaki, Jairaj K. Acharya, and Usha Acharya. "Sphingosine kinases and their metabolites modulate endolysosomal trafficking in photoreceptors." Journal of Cell Biology 192, no. 4 (February 14, 2011): 557–67. http://dx.doi.org/10.1083/jcb.201004098.

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Internalized membrane proteins are either transported to late endosomes and lysosomes for degradation or recycled to the plasma membrane. Although proteins involved in trafficking and sorting have been well studied, far less is known about the lipid molecules that regulate the intracellular trafficking of membrane proteins. We studied the function of sphingosine kinases and their metabolites in endosomal trafficking using Drosophila melanogaster photoreceptors as a model system. Gain- and loss-of-function analyses show that sphingosine kinases affect trafficking of the G protein–coupled receptor Rhodopsin and the light-sensitive transient receptor potential (TRP) channel by modulating the levels of dihydrosphingosine 1 phosphate (DHS1P) and sphingosine 1 phosphate (S1P). An increase in DHS1P levels relative to S1P leads to the enhanced lysosomal degradation of Rhodopsin and TRP and retinal degeneration in wild-type photoreceptors. Our results suggest that sphingosine kinases and their metabolites modulate photoreceptor homeostasis by influencing endolysosomal trafficking of Rhodopsin and TRP.

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Delehanty, James B., Christopher E. Bradburne, Kelly Boeneman, Kimihiro Susumu, Dorothy Farrell, Bing C. Mei, Juan B. Blanco-Canosa, et al. "Delivering quantum dot-peptide bioconjugates to the cellular cytosol: escaping from the endolysosomal system." Integrative Biology 2, no. 5-6 (2010): 265. http://dx.doi.org/10.1039/c0ib00002g.

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O'Leary, Robert, James E. Reilly, Hugo H. Hanson, Semie Kang, Nicole Lou, and Greg R. Phillips. "A variable cytoplasmic domain segment is necessary for γ-protocadherin trafficking and tubulation in the endosome/lysosome pathway." Molecular Biology of the Cell 22, no. 22 (November 15, 2011): 4362–72. http://dx.doi.org/10.1091/mbc.e11-04-0283.

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Clustered protocadherins (Pcdhs) are arranged in gene clusters (α, β, and γ) with variable and constant exons. Variable exons encode cadherin and transmembrane domains and ∼90 cytoplasmic residues. The 14 Pcdh-αs and 22 Pcdh-γs are spliced to constant exons, which, for Pcdh-γs, encode ∼120 residues of an identical cytoplasmic moiety. Pcdh-γs participate in cell–cell interactions but are prominently intracellular in vivo, and mice with disrupted Pcdh-γ genes exhibit increased neuronal cell death, suggesting nonconventional roles. Most attention in terms of Pcdh-γ intracellular interactions has focused on the constant domain. We show that the variable cytoplasmic domain (VCD) is required for trafficking and organelle tubulation in the endolysosome system. Deletion of the constant cytoplasmic domain preserved the late endosomal/lysosomal trafficking and organelle tubulation observed for the intact molecule, whereas deletion or excision of the VCD or replacement of the Pcdh-γA3 cytoplasmic domain with that from Pcdh-α1 or N-cadherin dramatically altered trafficking. Truncations or internal deletions within the VCD defined a 26–amino acid segment required for trafficking and tubulation in the endolysosomal pathway. This active VCD segment contains residues that are conserved in Pcdh-γA and Pcdh-γB subfamilies. Thus the VCDs of Pcdh-γs mediate interactions critical for Pcdh-γ trafficking.

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Sabitzki, Ricarda, Anna-Lena Roßmann, Marius Schmitt, Sven Flemming, Andrés Guillén-Samander, Hannah Michaela Behrens, Ernst Jonscher, Katharina Höhn, Ulrike Fröhlke, and Tobias Spielmann. "Role of Rabenosyn-5 and Rab5b in host cell cytosol uptake reveals conservation of endosomal transport in malaria parasites." PLOS Biology 22, no. 5 (May 31, 2024): e3002639. http://dx.doi.org/10.1371/journal.pbio.3002639.

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Vesicular trafficking, including secretion and endocytosis, plays fundamental roles in the unique biology of Plasmodium falciparum blood-stage parasites. Endocytosis of host cell cytosol (HCC) provides nutrients and room for parasite growth and is critical for the action of antimalarial drugs and parasite drug resistance. Previous work showed that PfVPS45 functions in endosomal transport of HCC to the parasite’s food vacuole, raising the possibility that malaria parasites possess a canonical endolysosomal system. However, the seeming absence of VPS45-typical functional interactors such as rabenosyn 5 (Rbsn5) and the repurposing of Rab5 isoforms and other endolysosomal proteins for secretion in apicomplexans question this idea. Here, we identified a parasite Rbsn5-like protein and show that it functions with VPS45 in the endosomal transport of HCC. We also show that PfRab5b but not PfRab5a is involved in the same process. Inactivation of PfRbsn5L resulted in PI3P and PfRab5b decorated HCC-filled vesicles, typical for endosomal compartments. Overall, this indicates that despite the low sequence conservation of PfRbsn5L and the unusual N-terminal modification of PfRab5b, principles of endosomal transport in malaria parasite are similar to that of model organisms. Using a conditional double protein inactivation system, we further provide evidence that the PfKelch13 compartment, an unusual apicomplexa-specific endocytosis structure at the parasite plasma membrane, is connected upstream of the Rbsn5L/VPS45/Rab5b-dependent endosomal route. Altogether, this work indicates that HCC uptake consists of a highly parasite-specific part that feeds endocytosed material into an endosomal system containing more canonical elements, leading to the delivery of HCC to the food vacuole.

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Balukova, Andrea, Kalliopi Bokea, Paul R. Barber, Simon M. Ameer-Beg, Alexander J. MacRobert, and Elnaz Yaghini. "Cellular Imaging and Time-Domain FLIM Studies of Meso-Tetraphenylporphine Disulfonate as a Photosensitising Agent in 2D and 3D Models." International Journal of Molecular Sciences 25, no. 8 (April 11, 2024): 4222. http://dx.doi.org/10.3390/ijms25084222.

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Fluorescence lifetime imaging (FLIM) and confocal fluorescence studies of a porphyrin-based photosensitiser (meso-tetraphenylporphine disulfonate: TPPS2a) were evaluated in 2D monolayer cultures and 3D compressed collagen constructs of a human ovarian cancer cell line (HEY). TPPS2a is known to be an effective model photosensitiser for both Photodynamic Therapy (PDT) and Photochemical Internalisation (PCI). This microspectrofluorimetric study aimed firstly to investigate the uptake and subcellular localisation of TPPS2a, and evaluate the photo-oxidative mechanism using reactive oxygen species (ROS) and lipid peroxidation probes combined with appropriate ROS scavengers. Light-induced intracellular redistribution of TPPS2a was observed, consistent with rupture of endolysosomes where the porphyrin localises. Using the same range of light doses, time-lapse confocal imaging permitted observation of PDT-induced generation of ROS in both 2D and 3D cancer models using fluorescence-based ROS together with specific ROS inhibitors. In addition, the use of red light excitation of the photosensitiser to minimise auto-oxidation of the probes was investigated. In the second part of the study, the photophysical properties of TPPS2a in cells were studied using a time-domain FLIM system with time-correlated single photon counting detection. Owing to the high sensitivity and spatial resolution of this system, we acquired FLIM images that enabled the fluorescence lifetime determination of the porphyrin within the endolysosomal vesicles. Changes in the lifetime dynamics upon prolonged illumination were revealed as the vesicles degraded within the cells.

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Otomo, Asako, Lei Pan, and Shinji Hadano. "Dysregulation of the Autophagy-Endolysosomal System in Amyotrophic Lateral Sclerosis and Related Motor Neuron Diseases." Neurology Research International 2012 (2012): 1–12. http://dx.doi.org/10.1155/2012/498428.

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Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of incurable motor neuron diseases (MNDs) characterized by a selective loss of upper and lower motor neurons in the brain and spinal cord. Most cases of ALS are sporadic, while approximately 5–10% cases are familial. More than 16 causative genes for ALS/MNDs have been identified and their underlying pathogenesis, including oxidative stress, endoplasmic reticulum stress, excitotoxicity, mitochondrial dysfunction, neural inflammation, protein misfolding and accumulation, dysfunctional intracellular trafficking, abnormal RNA processing, and noncell-autonomous damage, has begun to emerge. It is currently believed that a complex interplay of multiple toxicity pathways is implicated in disease onset and progression. Among such mechanisms, ones that are associated with disturbances of protein homeostasis, the ubiquitin-proteasome system and autophagy, have recently been highlighted. Although it remains to be determined whether disease-associated protein aggregates have a toxic or protective role in the pathogenesis, the formation of them results from the imbalance between generation and degradation of misfolded proteins within neuronal cells. In this paper, we focus on the autophagy-lysosomal and endocytic degradation systems and implication of their dysfunction to the pathogenesis of ALS/MNDs. The autophagy-endolysosomal pathway could be a major target for the development of therapeutic agents for ALS/MNDs.

Journal articles on the topic 'Endolysosomal system'

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