Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2014 May 1;6(5):a016931.
doi: 10.1101/cshperspect.a016931.

Role of endosomes and lysosomes in human disease

Frederick R Maxfield  1
Affiliations
Review

Role of endosomes and lysosomes in human disease

Frederick R Maxfield. Cold Spring Harb Perspect Biol. .

Abstract

In addition to their roles in normal cell physiology, endocytic processes play a key role in many diseases. In this review, three diseases are discussed as examples of the role of endocytic processes in disease. The uptake of cholesterol via LDL is central to our understanding of atherosclerosis, and the study of this disease led to many of the key breakthroughs in understanding receptor-mediated endocytosis. Alzheimer's disease is a growing burden as the population ages. Endosomes and lysosomes play important but only partially understood roles in both the formation and the degradation of the amyloid fibrils that are associated with Alzheimer's disease. Inherited lysosomal storage diseases are individually rare, but collectively they affect many individuals. Recent advances are leading to improved enzyme replacement therapy and are also leading to small-molecule drugs to treat some of these diseases.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Receptor-mediated endocytic pathway in nonpolarized mammalian cells. The main pathways following clathrin-mediated endocytosis are illustrated. The pH of various organelles and the kinetics of passage between organelles are shown. LDL and transferrin and their receptors are shown as examples. (Inset) Cholesterol, produced by hydrolysis of cholesteryl esters by lysosomal acid lipase, binds to NPC2 and then NPC1 as part of the mechanism to facilitate cholesterol exit from the digestive organelles.
Figure 2.
Figure 2.
A lysosomal synapse. When a macrophage encounters aggregated LDL in the blood vessel wall, it forms a tight seal using actin-dependent membrane rearrangements. The sealed area is acidified by V-ATPase proton pumps in the plasma membrane, and lysosomes fuse in the contact area. This creates an extracellular, acidic, hydrolytic compartment in which cholesteryl esters in the LDL are digested, and the cholesterol can then be taken up by the macrophage.
Figure 3.
Figure 3.
Processing of APP to form Aβ peptide. APP is secreted by a constitutive secretory pathway from the Golgi. While on the plasma membrane, APP can be cleaved by α-secretases in the middle of the Aβ peptide region, thus preventing formation of Aβ peptide. APP is internalized by clathrin-mediated endocytosis. In the early endosome system, probably in the ERC, APP can be cleaved by BACE1 to release the amino-terminal domain into the lumen of the endosome. The carboxy-terminal transmembrane fragment can be cleaved by the γ-secretase within the transmembrane segment, perhaps after retrograde transport back to the TGN. The amyloidogenic Aβ peptide is released into the lumen of the organelles. As discussed in the text, these various steps of proteolytic processing may take place in several different organelles because APP and the various enzymes are found throughout the secretory and endocytic pathways.
Figure 4.
Figure 4.
Regulation of lysosomal pH in microglia. Unlike most cells, quiescent microglia (left) maintain a pH of ∼6.0 in their lysosomes. This limits the hydrolytic activity of the lysosomal acid hydrolases, and there is very little degradation of fibrillar forms of Aβ in these weakly acidic lysosomes. The ClC-7 chloride transporter plays an important role in dissipating the electrical gradient produced by the proton-pumping V-ATPase. In quiescent microglia, only low levels of ClC-7 and its heterodimeric partner, Ostm1, are expressed, and most of the ClC-7 is degraded by an ER-associated degradation. When microglia are activated by MCSF, expression of both CLC-7 and Ostm1 is increased, and ClC-7 is delivered to lysosomes. This allows full acidification to pH 5.0, and internalized fibrillar Aβ can be digested efficiently.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Aisen P, Enns C, Wessling-Resnick M 2001. Chemistry and biology of eukaryotic iron metabolism. Int J Biochem Cell Biol 33: 940–959 - PubMed
    1. Angelini C, Semplicini C 2012. Enzyme replacement therapy for Pompe Disease. Curr Neurol Neurosci Rep 12: 70–75 - PubMed
    1. Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, et al. 2000. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6: 916–919 - PubMed
    1. Blennow K, Zetterberg H, Fagan AM 2012. Fluid biomarkers in Alzheimer disease. Cold Spring Harb Perspect Med 2: a006221. - PMC - PubMed
    1. Boissonneault V, Filali M, Lessard M, Relton J, Wong G, Rivest S 2009. Powerful beneficial effects of macrophage colony-stimulating factor on β-amyloid deposition and cognitive impairment in Alzheimer’s disease. Brain 132: 1078–1092 - PubMed

Publication types

LinkOut - more resources