Biochimica et Biophysica Acta 1851 (2015) 997–998
Contents lists available at ScienceDirect
Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbalip
Editorial
Preface to the Special Issue on brain lipids
Over 140 years ago, J.L.W. Thudichum, in his marvelous book entitled ‘The Chemical Constituents of the Brain’, pointed out that ‘the brain is the most diversified chemical laboratory of the animal body’ [1]. However, even the great Thudichum could not have imagined the vast diversity of the chemistry of the brain that has been uncovered over the past century. Of the chemical constituents, it is the lipids that are the subject of this Special Issue. Indeed, the brain is a veritable fat deposit — a typical human brain weighs about 3 lbs, or ~1.5 kg, of which two thirds is made of lipids, with a considerable portion of the lipids found in myelin. Since the brain contains virtually no triglycerides, the function of lipids in the brain is more-or-less restricted to their roles as membrane components and in signaling pathways (rather than as a source of energy). The composition of membrane lipids varies significantly between white matter (i.e. that part of the brain which contains mainly glia and myelinated axons) and gray matter (which largely contains cell bodies and few myelinated axons). As in most other tissues, glycerophospholipids, sphingolipids and cholesterol comprise the major lipid classes in the brain. To quote again from Thudichum “it (i.e. his study) scrutinizes the several chemical constituents of nerve-matter, and endeavors, by the study and consideration of the peculiarities of each, and their combination, to obtain sufficient insight into normal and abnormal chemical functions to enable us in time to guide or correct them”. With these prophetic words in mind, we now focus on understanding the roles of lipids in brain physiology and pathophysiology. This Special issue can be generally divided into two halves: the first (Simons, Prinetti and Gad) focuses on the role of lipids in normal brain function, and the second (Levade thru to Valerio) focuses on the role of lipids in pathophysiological conditions. The connecting chapter (Dawson), is vital to bridge the two major subject areas, as this chapter focuses on analytical techniques required to define lipid structures. It is not by chance that the Special Issue opens with a discussion of the role of the metabolism and function of lipids in myelin (Simons). The rapid conduction of nerve impulses, the key aspect of brain function, requires the coating of axons by myelin sheaths, which are lipidrich and differ in their composition from most other membranes in the body; indeed, cholesterol and sphingolipids make up as much as 60% of myelin lipids, allowing the close packing and tight organization of molecules within the membrane. The chapter provocatively characterizes lipids according to their putative functions in myelin biology. The following chapter by Prinetti follows the theme that the unique lipid composition of the brain (and not just of myelin) is vital to brain function, by focusing on the ability of brain lipids (particularly cholesterol and glycosphingolipids) to laterally segregate in the plane of the lipid membrane bilayer into lipid-driven membrane domains, and indicates that alterations in lipid homeostasis can lead to altered membrane
http://dx.doi.org/10.1016/j.bbalip.2015.04.003 1388-1981/© 2015 Elsevier B.V. All rights reserved.
organization, which may be common to several major brain diseases. The third chapter on the role of lipids in normal brain physiology (Asher), might seem out of place at first glance, since the chapter focuses on the roles of lipids in circadian control; much of the data discussed in this chapter was obtained from tissues of non-neurological origin. However, the chapter highlights an exciting and emerging area of lipidomics, that is to say, circadian lipidomics, in which levels of specific lipids change concomitantly with the circadian clock; surely such an approach will impact our understanding of the chemistry and biology of brain lipids in the not too distant future. The chapter on how to measure brain lipids (Dawson) rightly points out that rapid developments in analytical techniques have brought lipid research into the 21st century. While analytical techniques might not be considered by some to be the most exciting area of research, it should be stressed that recent advances in these techniques have allowed an appreciation that lipid complexity is vast, and would have given our old friend Thudichum much food for thought! The final five chapters all focus on the role of lipids in brain disease. The classical diseases of brain lipid metabolism are the sphingolipid storage diseases, which are discussed in the chapter by Levade; since sphingolipids are found at high levels in the brain, it is perhaps not surprising that defects in their degradation lead to severe neurological phenotypes. What is more surprising is that no two sphingolipid storage diseases have the same phenotypes, indicating that accumulation of particular sphingolipids in specific brain areas has quite distinct effects on brain physiology. Moreover, while accumulation of sphingomyelin in Niemann–Pick A and B disease, due to defective acid sphingomyelinase (ASM) activity, was described decades ago, it is only recently that a role of sphingomyelin in a number of other human diseases has been appreciated. Quite unexpectedly, ASM is now known to play a role in the etiology of major depression and anxiety disorder, and the molecular mechanisms of the relationship to ASM, and other enzymes of the sphingolipid pathway, are the focus of a fascinating chapter by Kornhuber et al. Lest the editor of this Special Issue be accused of being biased towards sphingolipids (which he readily admits he is!), the final three chapters focus on phosphoinositides (PIPs), and in particular the role of PIPs (Waugh) in a variety of neurological diseases such as Alzheimer's, Parkinson's, epilepsy, stroke, cancer, Charcot–Marie–Tooth neuropathies and neurodevelopmental conditions such as Lowe's syndrome, and on cholesterol. The role of cholesterol in myelin biogenesis is the subject of chapter 8 (Saher), a chapter which nicely complements the earlier chapter by Simons on the role of cholesterol in normal brain function; chapter 8 emphasizes the role of disorders of cholesterol metabolism that can lead to hypomyelination and neurodegeneration. Last, but by no means least, chapter 9 (Leoni), suggests a direct relationship between the impairment of
998
Editorial
cholesterol metabolism and Huntington's disease, and summarizes data showing that genes involved in the cholesterol biosynthetic pathway, and thus in regulating the amount of sterols, are reduced in animal models of Huntington's disease; the question of how this relates to CAG trinucleotide repeats is clearly the key mechanistic issue that needs to be addressed in this field. To close, let us go back to our hero, Thudichum, who stated that “The knowledge of the composition and properties of neuroplasm and of its constituents will aid us in devising modes of radical treatment in cases in which, at present, only tentative symptomatic measures are taken. In short, it is probable that by the aid of chemistry, many derangements of the brain and mind, which are at present obscure, will become accurately definable and amenable to precise treatment, and what is now an object of anxious empiricism will become one for the proud exercise of exact science”. This Special Issue is offered many years after Thudichum, and hopefully provides some indication of advances made in the exact science of the study of lipids in the brain. Reference [1] J.L.W. Thudichum, A Treatise on the Chemical Composition of the Brain, Hamden, 1874. (Republished in 1962 by Archon Books).
Tony Futerman is the The Joseph Meyerhoff Professor of Biochemistry, and head of the Nella and Leon Benoziyo Center for Neurological Diseases at the Weizmann Institute of Science in Rehovot, Israel. He runs a research laboratory of about 20 people that focuses on the cell biology and biochemistry of sphingolipids, a major lipid class in cells, and the roles that they play in health and disease. A major research area concerns understanding the pathological mechanisms at play in neuronopathic forms of Gaucher disease. Dr. Futerman was a member of the Editorial Board of the Journal of Biological Chemistry from 2000–2012, was the chair of the 2006 Gordon Conference on Glycolipid and Sphingolipid Biology and was the chair of the first Gordon Conference on Lysosomal Diseases held in 2011.
Anthony H. Futerman Weizmann Institute of Science, Rehovot 76100, Israel E-mail address: [email protected].
Contents lists available at ScienceDirect
Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbalip
Editorial
Preface to the Special Issue on brain lipids
Over 140 years ago, J.L.W. Thudichum, in his marvelous book entitled ‘The Chemical Constituents of the Brain’, pointed out that ‘the brain is the most diversified chemical laboratory of the animal body’ [1]. However, even the great Thudichum could not have imagined the vast diversity of the chemistry of the brain that has been uncovered over the past century. Of the chemical constituents, it is the lipids that are the subject of this Special Issue. Indeed, the brain is a veritable fat deposit — a typical human brain weighs about 3 lbs, or ~1.5 kg, of which two thirds is made of lipids, with a considerable portion of the lipids found in myelin. Since the brain contains virtually no triglycerides, the function of lipids in the brain is more-or-less restricted to their roles as membrane components and in signaling pathways (rather than as a source of energy). The composition of membrane lipids varies significantly between white matter (i.e. that part of the brain which contains mainly glia and myelinated axons) and gray matter (which largely contains cell bodies and few myelinated axons). As in most other tissues, glycerophospholipids, sphingolipids and cholesterol comprise the major lipid classes in the brain. To quote again from Thudichum “it (i.e. his study) scrutinizes the several chemical constituents of nerve-matter, and endeavors, by the study and consideration of the peculiarities of each, and their combination, to obtain sufficient insight into normal and abnormal chemical functions to enable us in time to guide or correct them”. With these prophetic words in mind, we now focus on understanding the roles of lipids in brain physiology and pathophysiology. This Special issue can be generally divided into two halves: the first (Simons, Prinetti and Gad) focuses on the role of lipids in normal brain function, and the second (Levade thru to Valerio) focuses on the role of lipids in pathophysiological conditions. The connecting chapter (Dawson), is vital to bridge the two major subject areas, as this chapter focuses on analytical techniques required to define lipid structures. It is not by chance that the Special Issue opens with a discussion of the role of the metabolism and function of lipids in myelin (Simons). The rapid conduction of nerve impulses, the key aspect of brain function, requires the coating of axons by myelin sheaths, which are lipidrich and differ in their composition from most other membranes in the body; indeed, cholesterol and sphingolipids make up as much as 60% of myelin lipids, allowing the close packing and tight organization of molecules within the membrane. The chapter provocatively characterizes lipids according to their putative functions in myelin biology. The following chapter by Prinetti follows the theme that the unique lipid composition of the brain (and not just of myelin) is vital to brain function, by focusing on the ability of brain lipids (particularly cholesterol and glycosphingolipids) to laterally segregate in the plane of the lipid membrane bilayer into lipid-driven membrane domains, and indicates that alterations in lipid homeostasis can lead to altered membrane
http://dx.doi.org/10.1016/j.bbalip.2015.04.003 1388-1981/© 2015 Elsevier B.V. All rights reserved.
organization, which may be common to several major brain diseases. The third chapter on the role of lipids in normal brain physiology (Asher), might seem out of place at first glance, since the chapter focuses on the roles of lipids in circadian control; much of the data discussed in this chapter was obtained from tissues of non-neurological origin. However, the chapter highlights an exciting and emerging area of lipidomics, that is to say, circadian lipidomics, in which levels of specific lipids change concomitantly with the circadian clock; surely such an approach will impact our understanding of the chemistry and biology of brain lipids in the not too distant future. The chapter on how to measure brain lipids (Dawson) rightly points out that rapid developments in analytical techniques have brought lipid research into the 21st century. While analytical techniques might not be considered by some to be the most exciting area of research, it should be stressed that recent advances in these techniques have allowed an appreciation that lipid complexity is vast, and would have given our old friend Thudichum much food for thought! The final five chapters all focus on the role of lipids in brain disease. The classical diseases of brain lipid metabolism are the sphingolipid storage diseases, which are discussed in the chapter by Levade; since sphingolipids are found at high levels in the brain, it is perhaps not surprising that defects in their degradation lead to severe neurological phenotypes. What is more surprising is that no two sphingolipid storage diseases have the same phenotypes, indicating that accumulation of particular sphingolipids in specific brain areas has quite distinct effects on brain physiology. Moreover, while accumulation of sphingomyelin in Niemann–Pick A and B disease, due to defective acid sphingomyelinase (ASM) activity, was described decades ago, it is only recently that a role of sphingomyelin in a number of other human diseases has been appreciated. Quite unexpectedly, ASM is now known to play a role in the etiology of major depression and anxiety disorder, and the molecular mechanisms of the relationship to ASM, and other enzymes of the sphingolipid pathway, are the focus of a fascinating chapter by Kornhuber et al. Lest the editor of this Special Issue be accused of being biased towards sphingolipids (which he readily admits he is!), the final three chapters focus on phosphoinositides (PIPs), and in particular the role of PIPs (Waugh) in a variety of neurological diseases such as Alzheimer's, Parkinson's, epilepsy, stroke, cancer, Charcot–Marie–Tooth neuropathies and neurodevelopmental conditions such as Lowe's syndrome, and on cholesterol. The role of cholesterol in myelin biogenesis is the subject of chapter 8 (Saher), a chapter which nicely complements the earlier chapter by Simons on the role of cholesterol in normal brain function; chapter 8 emphasizes the role of disorders of cholesterol metabolism that can lead to hypomyelination and neurodegeneration. Last, but by no means least, chapter 9 (Leoni), suggests a direct relationship between the impairment of
998
Editorial
cholesterol metabolism and Huntington's disease, and summarizes data showing that genes involved in the cholesterol biosynthetic pathway, and thus in regulating the amount of sterols, are reduced in animal models of Huntington's disease; the question of how this relates to CAG trinucleotide repeats is clearly the key mechanistic issue that needs to be addressed in this field. To close, let us go back to our hero, Thudichum, who stated that “The knowledge of the composition and properties of neuroplasm and of its constituents will aid us in devising modes of radical treatment in cases in which, at present, only tentative symptomatic measures are taken. In short, it is probable that by the aid of chemistry, many derangements of the brain and mind, which are at present obscure, will become accurately definable and amenable to precise treatment, and what is now an object of anxious empiricism will become one for the proud exercise of exact science”. This Special Issue is offered many years after Thudichum, and hopefully provides some indication of advances made in the exact science of the study of lipids in the brain. Reference [1] J.L.W. Thudichum, A Treatise on the Chemical Composition of the Brain, Hamden, 1874. (Republished in 1962 by Archon Books).
Tony Futerman is the The Joseph Meyerhoff Professor of Biochemistry, and head of the Nella and Leon Benoziyo Center for Neurological Diseases at the Weizmann Institute of Science in Rehovot, Israel. He runs a research laboratory of about 20 people that focuses on the cell biology and biochemistry of sphingolipids, a major lipid class in cells, and the roles that they play in health and disease. A major research area concerns understanding the pathological mechanisms at play in neuronopathic forms of Gaucher disease. Dr. Futerman was a member of the Editorial Board of the Journal of Biological Chemistry from 2000–2012, was the chair of the 2006 Gordon Conference on Glycolipid and Sphingolipid Biology and was the chair of the first Gordon Conference on Lysosomal Diseases held in 2011.
Anthony H. Futerman Weizmann Institute of Science, Rehovot 76100, Israel E-mail address: [email protected].
