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The cell biology of lysosomal storage disorders

Nature Reviews Molecular Cell Biology volume 5, pages 554–565 (2004)Cite this article

Key Points

  • Lysosomes are membrane-bound organelles that contain digestive enzymes that are responsible for the degradation of macromolecules such as proteins, lipids and carbohydrates.

  • Lysosomal storage disorders (LSDs) are a class of inherited metabolic diseases. They are caused by the defective activity of soluble lysosomal enzymes or integral membrane proteins, which results in the intra-lysosomal accumulation of undegraded metabolites.

  • A number of new proteins that are involved in LSDs have recently been identified, including an enzyme that is required for optimal sulphatase activity (defects in which cause multiple sulphatase deficiency) and soluble and integral membrane proteins that are involved in the ceroid lipofuscinoses.

  • Little is known about how and why the intra-lysosomal accumulation of undegraded metabolites causes disease pathology, but the extensive range of disease symptoms indicates that many secondary biochemical and cellular pathways are activated in different LSDs.

  • Potential changes in lysosomal stability and integrity, in intracellular trafficking and intracellular signalling, as well as alterations in secondary biochemical pathways and in gene expression, could be involved in LSD pathology.

  • The most effective treatment for LSDs would be somatic gene therapy, but the prospect of this becoming available soon is remote. At present, treatments are mainly limited to enzyme-replacement therapy and substrate-reduction therapy.

  • New therapies should arise as the secondary biochemical and cellular pathways that are altered in LSDs are elucidated.

Abstract

Lysosomal storage disorders, of which more than 40 are known, are caused by the defective activity of lysosomal proteins, which results in the intra-lysosomal accumulation of undegraded metabolites. Despite years of study of the genetic and molecular bases of lysosomal storage disorders, little is known about the events that lead from this intra-lysosomal accumulation to pathology. Here, we summarize the biochemistry of lysosomal storage disorders. We then discuss downstream cellular pathways that are potentially affected in these disorders and that might help us to delineate their pathological mechanisms.

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Figure 1: The defect in multiple sulphatase deficiency.
Figure 2: The biochemical and cellular basis of lysosomal storage disorders.
Figure 3: A possible roadmap of the pathology of lysosomal storage disorders.
Figure 4: Therapies for lysosomal storage disorders.

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Authors and Affiliations

  1. Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel

    Anthony H. Futerman

  2. Department of Membrane Enzymology, Institute of Biomembranes, Utrecht University, Utrecht, 3584 CH, The Netherlands

    Gerrit van Meer

Authors
  1. Anthony H. Futerman
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  2. Gerrit van Meer
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DATABASES

Nobel e-museum

Christian de Duve — Nobel lecture

Saccharomyces genome database

Btn1

Btn2

Yif1

Swiss-Prot

ABC1

ABC2

ABC9

acid sphingomyelinase

cathepsin A

cathepsin D

CLN1

CLN2

CLN3

CLN5

CLN6

CLN8

γ-COP

CTP:phosphocholine cytidylyltransferase

ERGIC53

FGE

PPT2

Glossary

MANNOSE-6-PHOSPHATE RECEPTORS

Receptors that are located at the trans-Golgi network and, at low levels, at the plasma membrane. They are responsible for targeting several soluble lysosomal hydrolases from the Golgi, through endosomes, to lysosomes.

SPHINGOMYELIN

A sphingolipid that contains a phosphorylcholine headgroup.

GLYCOSAMINOGLYCANS

Long, linear, charged polysaccharides that are composed of a repeating pair of sugars, of which one is an amino sugar.

SPHINGOLIPIDS

Membrane lipids containing a ceramide backbone. Ceramide consists of a long chain sphingoid base, to which a fatty acid is linked through the amino group at C2. A headgroup is linked to the hydroxyl at C1.

GANGLIOSIDE

A sialic-acid-containing glycosphingolipid that accumulates in the gangliosidoses.

ABC TRANSPORTERS

A family of membrane transport proteins that use the energy of ATP hydrolysis to transport various molecules across the membrane.

UNFOLDED PROTEIN RESPONSE

A cellular response that is triggered by the accumulation of misfolded proteins in the endoplasmic reticulum (ER) and that results in the transcriptional upregulation of ER chaperones and degradative enzymes.

LYSOSOMOTRPHIC AGENTS

Molecules that move to the lysosome: mostly weak bases that diffuse across the lysosomal membrane as uncharged molecules and are trapped inside in their protonated form due to the low pH.

EXOSOMES

50–80-nm membrane vesicles that are secreted into the extracellular milieu as a consequence of multivesicular-body fusion with the plasma membrane.

GLYCOSPHINGOLIPID

A sphingolipid with an oligosaccharide headgroup. The sugar that is linked to the ceramide lipid backbone is generally glucose, but is galactose in galactosylceramide and sulphatide.

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Futerman, A., van Meer, G. The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol 5, 554–565 (2004). https://doi.org/10.1038/nrm1423

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