Even though many details remain to be resolved, a striking body of evidence indicates that disturbed vesicular trafficking has special relevance in AD and other neurodegenerative diseases [ 3 ]. In particular, as just described, early endosomes mark the location of initial amyloidogenic processing of APP by beta-site APP cleaving enzyme 1 BACE1 and dissociation of ApoE from its receptor, LDLR1, upon internalization and the extent to which these events occur is dependent upon the time of residence in this compartment, thus attracting much attention.
ApoE and its receptor genetically and functionally interact with APP, to influence its endocytosis and degradation [ 34 , 35 ], thereby modulating the severity of amyloid pathogenesis.
In the brains of AD patients, Cataldo et al. As a consequence, it has been noted that ectopic, elevated levels of lysosomal hydrolases can be observed in the CSF of individuals with AD [ 41 ]. It was first reported almost two decades ago that in familial AD, Rab5 is overexpressed or stabilized post-translationally concommitant with a very marked increase in pyramidal neuron early endosome volume, and this results in increased processing of APP, a sorting imbalance, and decreases in neurotrophin receptor expression [ 42 , 43 ].
Enlargement of the early endosome compartment has been considered as the earliest pathological change in AD, even occurring decades before clinical symptoms are evident [ 44 ]. Further, swollen endosomal profiles have been postulated to represent activation of the endosomal-lysosomal pathway, involving increased rates of endocytosis and vesicular turnover.
Consistent with this, studies using Rab5 as a specific endosomal marker have identified a relationship between increased endocytosis and an enlargement in endosome size and volume [ 45 ]. Another recent review that delves into effects of interactors in regulating traffic of APP and secretases, particularly considering events increasing their co-location throughout the endomembrane system as opportunities for alternative APP processing events [ 47 ].
Even though it is established that AD is a heterogeneous disease, perturbation of the neuronal endosomal-lysosomal pathway is one cellular feature shared in common by all subtypes of AD. Therefore, it is tempting to speculate that cellular pathological changes affecting this system are early and essential initiating events in AD pathogenesis, regardless of disease subtype and genetic predisposition.
Endosomal-lysosomal pH defects are an emerging theme in mechanisms underlying a number of neurodegenerative diseases. To date, results from experiments in vivo and in vitro have revealed the importance of proper vesicular pH balance and optimal acidification in transporting and degrading cargo via the endocytic pathway [ 48 , 49 ].
For instance, Lee et al. Specifically, dysregulation of acidification and intracellular pH perturbation could influence the activity of enzymes in endomembrane compartments, resulting in impaired clearance of protein aggregates downstream of elevated endomembrane system pH, or conversely, due to decreased cytoplasmic pH. Regarding the latter, asparaginyl endopeptidase AEP is a typical pH-sensitive protein hydrolase the activity of which depends on the acidic pH of vesicular compartments.
Predominantly localized in late endosomes, asparaginyl endopeptidase AEP specifically cleaves substrates with an asparagine residue at the P1 site. It is known that AEP can undergo reversible pH-dependent autoproteolytic activation, and in normal conditions, full-length pro-AEP is inactive [ 51 ]. As pH decreases from neutral to acidic, the activity of AEP gradually increases, such that it is partially activated at pH 4.
In AD patients, lysosomal acidification may be defective and it has been shown that the intracellular pH of neurons gradually decreases with aging [ 52 ] and more so with lactic acid elevation seen in AD cortex [ 53 ], so ectopic AEP activation or activity after leakage of active enzyme from late endosomes or lysosomes may be increased.
AEP is involved in pathological tau degradation. Specifically, AEP generates tau fragments that form insoluble fibrils and result in neurotoxicity and neuropathological changes in AD [ 54 , 55 ].
Increased endosome and lysosome pH is expected to have global effects on the proteome, particularly membrane proteins which rely on this pathway for their regulation and degradation. Indeed, blocking lysosomal degradation with bafilomycin A1 affects a significant increase in global K63 polyubiquitin linkages, which also occurs in AD, but AD brain global ubiquitin linkage profiling shows changes in other linkages as well [ 59 ].
Since K63 linked ubiquitin is not targeted to the proteasome, but does increase with V-ATPase acidification in the model of lysosomal insufficiency, the increase in K63 linkages seen in AD implicates accumulation of ubiquitinated proteins with obligate ESCRT-mediated degradation.
Thus, trafficking, inflammatory signaling, and cell-type specific roles of dynamic lysosomal acidification are becoming increasingly appreciated for potential roles in AD pathogenesis. A number of neurodegenerative diseases, including AD, are characterized by accumulation of intracellular ubiquitinated proteins which can be actively collected into aggregates that are usually targeted to autophagosomes, thus implicating defective autophagy.
The ESCRT complexes are involved in multiple cellular processes, including efficient fusion of autophagic vesicles for bulk degradation of cargo proteins. Autophagy serves as an intracellular clearance mechanism, preventing the accumulation of proteins that disrupt neuronal function and eventually lead to neurodegeneration [ 60 , 61 ].
Interestingly, in early stages of AD, autophagy in neurons is activated, but becomes compromised as the disease progresses. There are more and more studies to identify the signal molecular machinery involving autophagy and the ESCRTs. Studies indicate that the ESCRT machinery is not only involved in sorting ubiquitinated cargo but also in initiating vesicle formation within endosomes becoming MVBs [ 62 ]. CHMP2B overexpression in neurons impairs lysosomal degradation of internalized proteins, resulting in accumulation of autophagosome, dendritic retraction and neuronal loss [ 63 ].
Typically, the autophagic pathway converges with the endocytic pathway at a point where mature autophagosomes fuse with MVBs. Compromised ESCRT function blocks the maturation and the proper turnover of autophagosomes, while functional ESCRT complexes are required for autophagic fusion and efficient degradation [ 64 , 65 ]. Over the years, researchers have studied neurodegenerative diseases arising from defects of retromer sorting proteins [ 66 — 68 ].
Particular interest has been taken in the link between retromer function to AD pathogenesis [ 69 ]. In the brains of patients with AD, expression of Vps26 and Vps35 is reduced. Since these are two critical components of the retromer CSC trimer that recognize retromer cargo including BACE1, loss of function for the CSC would be expected to promote amyloidogenesis.
Interestingly, the above mentioned chemical chaperone also shifted the localization of SorLA, which associates with both Vps26 and APP, modulating amyloidogenic cleavage of APP [ 74 ] by upregulating the sorting of APP into endosomal compartments [ 75 ]. In cultured hippocampal neurons, studies have confirmed important roles of SorLA in trafficking and processing of APP. Finally, it is important to point out that the general processes of endocytosis and endosomal-lysosomal dysregulations above-mentioned, have profoundly distinct implications for potential functions associated with other neurodegenerative diseases, such as PD, ALS, and Frontotemporal lobe degeneration FTLD.
In recent years, particular attention has been paid to the endosomal-lysosomal system because it is involved in almost all of the neurodegenerative diseases, even though how it does so in each still remains unclear. Ongoing future studies will investigate both common and cell-type or even local membrane region specific trafficking and proteostasis pathways involving the endosomal-lysosomal system as well as the larger endomembrane system. For example, a better understanding of distinct roles that ubiquitination plays in ESCRT-mediated proteostasis and even lipid droplet homeostasis [ 79 ] which appears to be dysregulated in glia in neurodegeneration [ 47 , 80 ] could help to predict and ultimately therapeutically address the onset and progression of neurodegenerative diseases for specific individuals or sub-populations.
This milieu of membrane-bound proteins that dynamically sorts cargo enriched for signaling, inflammation, and neurotrophic functions—among others—promises to provide a mother lode of new therapeutic targets for amelioriating neurodegenerative diseases, but the exploration also promises to be challenging, requiring the development of novel techniques and insight.
Tan J, Evin G. Beta-site APP-cleaving enzyme 1 trafficking and Alzheimer's disease pathogenesis. J Neurochem. Neefjes J, van der Kant R. Stuck in traffic: an emerging theme in diseases of the nervous system.
Trends Neurosci. Endocytosis and autophagy: exploitation or cooperation? Cold Spring Harb Perspect Biol. Article PubMed Google Scholar. Endocytosis and autophagy: Shared machinery for degradation. Huotari J, Helenius A. Endosome maturation. EMBO J. Diering GH, Numata M. Frontiers in Physiology. Rab-mediated trafficking role in neurite formation. Rab5 mediates an amyloid precursor protein signaling pathway that leads to apoptosis.
J Neurosci. Li X, DiFiglia M. The recycling endosome and its role in neurological disorders. Prog Neurobiol. Hsu VW, Prekeris R. Transport at the recycling endosome. Curr Opin Cell Biol. Identification of the switch in early-to-late endosome transition. Raiborg C, Stenmark H. Endolysosomal proteolysis and its regulation. Biochem J. Isolation and characterization of early endosomes, late endosomes and terminal lysosomes: their role in protein degradation.
J Cell Sci. A model of lysosomal pH regulation. J Gen Physiol. Endosome-lysosome fusion. Biochem Soc Trans. Membrane trafficking in neuronal maintenance and degeneration. Cell Mol Life Sci. Maxson ME, Grinstein S. Breton S, Brown D. Regulation of luminal acidification by the V-ATPase. Physiology Bethesda. CAS Google Scholar. Morel N, Poea-Guyon S. Bafilomycin A1 targets both autophagy and apoptosis pathways in pediatric B-cell acute lymphoblastic leukemia. Inhibition of macroautophagy by bafilomycin A1 lowers proliferation and induces apoptosis in colon cancer cells.
Biochem Biophys Res Commun. Stauber T, Jentsch TJ. J Biol Chem. Curr Biol. Physiological functions of CLC Cl- channels gleaned from human genetic disease and mouse models.
Holtzman, E. Lysosomes Plenum, New York, Book Google Scholar. De Reuck, A. Churchill, London, Google Scholar. Mellman, I. Acidification of the endocytic and exocytic pathways.
Helenius, A. Trends Biochem. Endocytosis and molecular sorting. Cell Dev. Mukherjee, S. Storrie, B. The biogenesis of lysosomes: is it a kiss and run, continuous fusion and fission process? Bioessays 18 , — Luzio, J. Lysosome—endosome fusion and lysosome biogenesis. Cell Sci. Mullins, C. The molecular machinery for lysosome biogenesis. Bioessays 23 , — Membrane dynamics and the biogenesis of lysosomes.
Bright, N. Endocytic delivery to lysosomes mediated by concurrent fusion and kissing events in living cells. A study showing that the transfer of contents between endosomes and lysosomes occurs by kissing events and direct fusion in living cells.
Pryor, P. Cell Biol. Ghosh, P. Mannose 6-phosphate receptors: new twists in the tale. Nature Rev. Seaman, M. Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer.
Doray, B. Science , — Bonifacino, J. The GGA proteins: adaptors on the move. Peden, A. Localization of the AP-3 adaptor complex defines a novel endosomal exit site for lysosomal membrane proteins. Ihrke, G. Differential use of two APmediated pathways by lysosomal membrane proteins. Traffic 5 , — Salazar, G. BLOC-1 complex deficiency alters the targeting of adaptor protein complex-3 cargoes.
Cell 17 , — Di Pietro, S. Pak, Y. Haglund, K. Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Huang, F. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Cell 21 , — Murphy, R. Maturation models for endosome and lysosome biogenesis. Trends Cell Biol. Stoorvogel, W. Late endosomes derive from early endosomes by maturation.
Cell 65 , — Gu, F. Biogenesis of transport intermediates in the endocytic pathway. FEBS Lett. Rink, J. Rab conversion as a mechanism of progression from early to late endosomes. Cell , — Gillooly, D. Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells.
EMBO J. White, I. EGF stimulates annexin 1-dependent inward vesiculation in a multivesicular endosome subpopulation. Gruenberg, J. The biogenesis of multivesicular endosomes. Bowers, K. Protein transport from the late Golgi to the vacuole in the yeast Saccharomyces cerevisiae. Acta , — Slagsvold, T. Hurley, J. Kostelansky, M. Chu, T. Oestreich, A.
Cell Curtiss, M. Horii, M. Degradation of endocytosed epidermal growth factor and virally ubiquitinated major histocompatibility complex class I is independent of mammalian ESCRTII. Langelier, C.
Bache, K. Hirst, J. The kinetics of mannose 6-phosphate receptor trafficking in the endocytic pathway in HEp-2 cells: the receptor enters and rapidly leaves multivesicular endosomes without accumulating in a prelysosomal compartment.
Cell 9 , — Aniento, F. Cytoplasmic dynein-dependent vesicular transport from early to late endosomes. Ward, D. Syntaxin 7 and VAMP-7 are soluble N -ethylmaleimide-sensitive factor attachment protein receptors required for late endosome—lysosome and homotypic lysosome fusion in alveolar macrophages. Cell 11 , — Futter, C. Multivesicular endosomes containing internalized EGF—EGF receptor complexes mature and then fuse directly with lysosomes. Electron-microscopic study that supports the concept of direct fusion between late endosomes and lysosomes and also demonstrates tethers between the organelles.
Dense core lysosomes can fuse with late endosomes and are re-formed from the resultant hybrid organelles. Mullock, B. Fusion of lysosomes with late endosomes produces a hybrid organelle of intermediate density and is NSF dependent.
Delivery to lysosomes in the human carcinoma cell line HEp-2 involves an actin filament-facilitated fusion between mature endosomes and preexisting lysosomes. Reconstitution of an endosome—lysosome interaction in a cell-free system.
Caplan, S. Human Vam6p promotes lysosome clustering and fusion in vivo. Poupon, V. The role of mVps18p in clustering, fusion, and intracellular localization of late endocytic organelles.
Cell 14 , — Richardson, S. Mammalian late vacuole protein sorting orthologues participate in early endosomal fusion and interact with the cytoskeleton.
Cell 15 , — Bucci, C. Rab7: a key to lysosome biogenesis. Marsman, M. A splice variant of RILP induces lysosomal clustering independent of dynein recruitment. Jordens, I. The Rab7 effector protein RILP controls lysosomal transport by inducing the recruitment of dynein—dynactin motors.
Falcon-Perez, J. Distribution and dynamics of Lamp1-containing endocytic organelles in fibroblasts deficient in BLOC Weber, T. SNAREpins: minimal machinery for membrane fusion.
Cell 92 , — Bock, J. A genomic perspective on membrane compartment organization. Nature , — Yoshizawa, A. Traffic 7 , — Jahn, R. Ultimately, the late endosomes fuse with lysosomes.
The lysosome is a membrane-enclosed vacuole in the cytoplasm, containing hydrolytic enzymes. The main function of a lysosome is to help in the digestion of biomolecules like nucleic acids, peptides, carbohydrates, lipids, etc. The hydrolytic enzymes in the lysosome come from the endoplasmic reticulum.
They travel to the cis phase of the Golgi apparatus by packaging in secretory vesicles. Finally, these enzymes leave the trans phase of the Golgi apparatus as lysosomes. Figure 2: Formation of Lysosomes. Furthermore, the pH of the cytoplasm is around 7. However, the pH inside a lysosome is 4. That means; the internal environment of the lysosome is acidic. It is due to the requirement of an acidic pH by the action of the hydrolytic enzymes in the lysosome.
Endosome refers to a vesicle formed by the invagination and pinching off of the cell membrane while lysosome is an organelle in the cytoplasm of eukaryotic cells containing degradative enzymes enclosed in a membrane. Hence, this is the fundamental difference between endosome and lysosome. Moreover, the formation is a major difference between endosome and lysosome. Endosomes, mainly, form during endocytosis while lysosomes form from Golgi apparatus.
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