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  • Review Article
  • Published:

Storage solutions: treating lysosomal disorders of the brain

Nature Reviews Neuroscience volume 6, pages 713–725 (2005)Cite this article

Key Points

  • Neurodegenerative diseases fall into two general categories: the idiopathic diseases that are associated with ageing (for example, Alzheimer's disease and Parkinson's disease) and the less common disorders that typically present in infancy or childhood, which result from monogenic defects (for example, Tay–Sachs disease). It is highly likely that unravelling the underlying pathological processes in both classes of disorder will have broad implications for the understanding and clinical management of neurodegenerative diseases as a whole.

  • This review focuses on a family of monogenic neurodegenerative diseases, the lysosomal storage disorders. These typically result from the autosomal recessive inheritance of defects in one of the genes that encode a catabolic lysosomal enzyme. The substrate for the defective enzyme accumulates, and complex downstream pathogenic pathways are activated, leading to cellular dysfunction and, ultimately, cell death.

  • These diseases have a high degree of clinical heterogeneity, and neuropathological symptoms include developmental delay, abnormal ocular movements, ataxia, seizures, movement disorders, spasticity, visual loss and psychiatric disease.

  • Much recent progress has been made in understanding the pathogenic cascades that are triggered by lysosomal storage, and many storage disorders have been shown to share pathological features with the common neurodegenerative diseases — for example, atypical inflammation in the CNS, altered calcium homeostasis and altered endosomal/lysosomal function.

  • The availability of spontaneous and engineered animal models of storage diseases has led to considerable advances in therapy, many of which are in clinical use or in clinical trials. One example of a new therapeutic approach is substrate reduction therapy (miglustat; Zavesca; Celltech/Actelion), which has been approved for use in the most common glycosphingolipid storage disease, type 1 Gaucher disease. Substrate reduction therapy is in clinical trials for neuronopathic storage diseases such as type 3 Gaucher disease, late-onset Tay–Sachs disease and Niemann–Pick disease type C. Experimental approaches such as gene therapy and neural stem cell therapy are currently being evaluated in animal disease models.

  • The storage of molecules, either in the lysosome or at extra-lysosomal sites, is a common hallmark of many neurodegenerative conditions. The challenge now is to determine whether the failure to degrade molecules leads to a common response in the brain. This offers the prospect of developing therapies that, in the future, could be used to treat several neurodegenerative disorders.

Abstract

Many neurodegenerative diseases are characterized by the accumulation of undegradable molecules in cells or at extracellular sites in the brain. One such family of diseases is the lysosomal storage disorders, which result from defects in various aspects of lysosomal function. Until recently, there was little prospect of treating storage diseases involving the CNS. However, recent progress has been made in understanding these conditions and in translating the findings into experimental therapies. We review the developments in this field and discuss the similarities in pathological features between these diseases and some more common neurodegenerative disorders.

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Figure 1: Glycosphingolipid storage in mice with Sandhoff disease.
Figure 2: Neuroinflammation — the point of convergence for distinct neurodegenerative disorders.

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Acknowledgements

We thank H. Perry, D. Sillence, E.-L. Evans and N. Platt for helpful comments on the manuscript. M.J. is supported by the Wellcome Trust and the Glycobiology Institute, University of Oxford, UK.

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Authors and Affiliations

  1. Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK

    Mylvaganam Jeyakumar, Raymond A. Dwek, Terry D. Butters & Frances M. Platt

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  1. Mylvaganam Jeyakumar
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  2. Raymond A. Dwek
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  3. Terry D. Butters
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Correspondence to Frances M. Platt.

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T.B., R.A.D. and F.P. have received a grant from Celltech.

Supplementary information

Supplementary information S1

Lysosomal storage disorders classified according to molecular defect. Reproduced, with permission, from REF. 1 © (2004) Oxford University Press. (PDF 125 kb)

1. Platt, F. M. & Walkley, S. U. in Lysosomal Disorders of the Brain: Recent Advances in Molecular and Cellular Pathogenesis and Treatment (eds Platt, F. M. & Walkley, S. U.) (Oxford Univ. Press, Oxford, 2004).

Related links

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DATABASES

OMIM

Alzheimer's disease

amyotrophic lateral sclerosis

type 1 Gaucher disease

type 2 Gaucher disease

type 3 Gaucher disease

Huntington's disease

Krabbe disease

Niemann–Pick disease type C1

Parkinson's disease

Sandhoff disease

Tay–Sachs disease

FURTHER INFORMATION

Global Organisation for Lysosomal Diseases (GOLD)

Human Gene Mutation Database, gene lesions for human inherited disease

Inborn Errors in Metabolism web site

National Organisation for Rare Diseases

The European Study Group on Lysosomal Storage Diseases

Glossary

FOUNDER EFFECT

The introduction of a mutant gene into an isolated population by a founder individual, which leads to the spread of the mutant allele within the population. This causes disease in subsequent generations and an above average carrier frequency in that population.

HEPATOSPLENOMEGALY

Enlargement of the liver and spleen.

PULSE-CHASE LABELLING STUDIES

A label is used to tag the molecules of interest and the cells are then analysed over time to track their distribution and ultimate fate. The experiment also allows estimation of the half-life of the molecules of interest.

FRIEDREICH'S ATAXIA

An autosomal recessive disease that is characterized by CNS dysfunction leading to ataxia. Typically, the first symptoms occur in early childhood or adolescence.

ER CHAPERONE BiP

BiP is a homologue of heat shock protein 70. It is found in the endoplasmic reticulum of eukaryotic cells and facilitates protein folding.

IMMUNOLOGICALLY SILENT

Molecules that do not normally trigger an immune response — for example, 'self' components that must be 'ignored' by the immune system to avoid autoimmune disease.

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Jeyakumar, M., Dwek, R., Butters, T. et al. Storage solutions: treating lysosomal disorders of the brain. Nat Rev Neurosci 6, 713–725 (2005). https://doi.org/10.1038/nrn1725

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