The pathogenesis of glycosphingolipid storage disorders

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Abstract

Glycosphingolipid storage disorders are inborn errors of metabolism caused by the defective activity of degradative enzymes in lysosomes. In this review, we summarize studies performed over the past few years attempting to define the secondary and down-stream biochemical and cellular pathways affected in GSL storage disorders that are responsible for neuronal dysfunction, a characteristic of most of these disorders. We focus mainly on the regulation of intracellular calcium homeostasis and phospholipid biosynthesis. These studies may help unravel new roles for glycosphingolipids in the regulation of normal cell physiology, as well as suggest potential new therapeutic options in the glycosphingolipid and other lysosomal storage disorders.

Introduction

Glycosphingolipids (GSLs) are essential components of eukaryotic cell membranes. They are synthesized in the endoplasmic reticulum (ER) and Golgi apparatus [1], reside mainly on the outer leaflet of the plasma membrane, are internalized by endocytosis [2], and are degraded in lysosomes. Although GSLs were once considered to be mainly structural components of membranes, they are now known to play important roles in a large number of regulatory events even though our knowledge of their precise roles in vivo remains incomplete. GSLs are vital to life [3], [4], consistent with the lack of known human diseases resulting from defective GSL biosynthesis. However, a number of inherited human metabolic disorders are known to result from defects in the lysosomal enzymes involved in GSL degradation (Fig. 1). These GSL storage disorders belong to a family of more than 40 known lysosomal storage disorders (LSDs) [5] in which the substrates of the defective enzymes accumulate in lysosomes. Interestingly, GSLs also accumulate in some LSDs secondarily to accumulation of the primary storage material [6]. For instance, brain storage of gangliosides GM2 and GM3 has been documented in Niemann-Pick type A disease, in which the primary storage material is sphingomyelin (SM) [7], [8], in Niemann-Pick type C disease, where the primary storage material appears to be cholesterol [9], [10], and also in mucopolysaccharidoses type I [11] and III [12], [13], where the primary storage materials are dermatan sulphate and heparan sulphate.

In this review we will discuss recent work attempting to delineate how GSL accumulation in various GSL storage diseases leads to cell pathology. Surprisingly, little is known about this, and it is our contention that understanding the mechanistic relationship between GSL accumulation and disease development will help not only in determining the underlying causes of the diseases but also the roles of GSLs in normal cell physiology.

Section snippets

Overview of disease pathogenesis

The frequency of individual GSL storage diseases is not high, but together they are a significant group of disorders with a collective frequency of 1 in 18 000 live births, and are the commonest cause of pediatric neurodegenerative diseases [14]. The clinical course and the severity of individual diseases differ widely between each other, but some common principles can be derived, with the clinical severity in general correlating with levels of residual enzyme activity [15]. When little or no

Is the ‘psychosine hypothesis’ sufficient to explain neuropathology in the GSL storage diseases?

Before dealing with these mechanistic questions in detail, we would like to discuss a hypothesis that has gained wide attention over the past 2–3 decades, and is accepted by some as the last word in explaining GSL storage disease pathology, namely the ‘psychosine hypothesis’, first suggested by Kuni Suzuki for Krabbe disease [28]. This hypothesis suggests that lyso-GSLs (i.e. GSLs devoid of the N-acylated fatty acid) are the primary cause of GSL storage disease pathology. In Krabbe disease,

A role for calcium in GSL storage disease pathogenesis

Calcium plays an important role in regulating a great variety of neuronal processes. The mechanisms responsible for regulating cytosolic Ca2+ concentration involve external Ca2+-influx via voltage- and ligand-gated channels in the plasma membrane along with release of calcium from intracellular stores [42], [43]. In excitable cells, Ca2+ induces immediate responses such as muscle contraction or neurotransmitter release, and Ca2+ can induce long-term responses via activation of signal

The possible relationship between altered Ca2+-homeostasis and GSL storage disorder pathology

A number of biochemical pathways are known to be activated upon either depletion of ER Ca2+ stores on upon elevation of cytosolic Ca2+ levels, and we speculate that activation of one or other of these pathways may be down-stream responses to GSL accumulation. For instance, upon depletion of ER Ca2+ stores, cells can enter a form of ER stress, the ‘unfolded protein response’ (UPR), which causes suppression of global protein synthesis, activation of stress gene expression, and induction of

Do GSLs accumulate in the ER, and if so, what are the possible physiological consequences?

A potentially valid criticism of our hypothesis that altered Ca2+-homeostasis mediated by ER Ca2+-channels and pumps is responsible for GSL storage disease neuropathology is that GSLs do not normally accumulate in the ER [1]. GSLs are synthesized distal to the ER, in the Golgi apparatus [102], and from there travel by vesicular transport to the PM, from which they are internalized by endocytosis by mechanisms involving caveolin- and clathrin-mediated pathways [2]. According to this classical

How might understanding disease pathogenesis help in the development of new therapies?

In the sections above, we have summarized progress in understanding the molecular basis of the GSL storage disorders. Might these findings be of any practical use in terms of development of therapies for these diseases, and indeed is there a need for development of new or alternative therapies? Two major therapies currently exist for GSL storage disorders, namely enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). The goal of both treatments is to reduce GSL storage, thus

Perspectives

In summary, the findings presented in this review shed light on the molecular mechanisms causing neuropathophysiology in the GSL storage diseases. Specifically, perturbing intracellular Ca2+-homeostasis and alterating phospholipid biosynthesis, in conjunction with other, as-yet unknown factors or pathways, may be responsible at the molecular level for some of the neuropathology observed in these diseases. Moreover, study of cell and tissue dysfunction in GSL storage diseases should lead to the

Acknowledgements

Work in the authors’ laboratory is supported by the Israel Science Foundation, the European Union (HPRN-CT-2000-00077), the Children’s Gaucher Research Fund, the estate of Louis Uger, Canada, and the National Niemann-Pick Disease Foundation. A.H. Futerman is The Joseph Meyerhoff Professor of Biochemistry at the Weizmann Institute of Science.

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