Editorial: A Trends guide to Neurodegenerative Disease and Repair

Abstract

A recent estimate suggests that the number of people over 65 years-of-age in the USA will double between now and the year 2050. Clearly, our population is aging, and aging brings with it the increased likelihood of neurodegenerative disease (ND). As a consequence, one of the great challenges of biomedical research will be to develop successful therapeutic strategies to enable us to enjoy our old age – not just to live longer, but to live longer in health.The field of NDs is too vast to be able to cover each and every topic in this special issue, but our aim was to discuss important recent advances and highlight some of the more encouraging therapeutic approaches.Protein accumulation and potential therapeutic targetsThe most common forms of age-related NDs are Alzheimer's disease (AD) and Parkinson's disease (PD), and both are characterized by abnormal protein aggregation. AD is characterized by the formation of Aβ-containing plaques, which involves γ-secretase cleavage of a precursor protein. The identity of this enzyme is currently uncertain, but presenilins are popular candidates. On pages S2–S6, Sangram Sisodia discusses the evidence for and against presenillins, and describes how their role in the CNS is more complex than we originally thought.An important question is why these toxic proteins accumulate – why are they not eliminated? It is emerging that an overwhelmed ubiquitin-dependent proteolysis system might well be responsible, as described by Ted Dawson (pages S7–S14).Insights from molecular analysisClearly, many NDs involve both genetic and environmental factors, and transgenic animals are one of the most widely used methods for studying genetic mutations and their pathological effects. Serge Przedborski outlines the major areas of progress resulting from the numerous animal models of Parkinson's disease, in which some of the more detailed aspects of the disease are revealed (pages S49–S55).Two other NDs for which the molecular basis is beginning to emerge are Huntington's disease (HD) and amytrophic lateral sclerosis (ALS), a progressive ND of motor neurons. HD is characterized by a CAG expansion that encodes a polyglutamine tract, which results in progressive protein accumulation. Cynthia McMurray's pioneering work in discovering the mechanism by which the CAG expansion occurs (see pages S32–S38) offers a new potential therapeutic target with implications beyond HD itself. And on pages S15–S20, Joe Beckman explains how zinc deficiency in the superoxide dismutase enzyme might underlie most, if not all, cases of ALS.Repair strategiesWhat is the best way to target the genetic abnormalities when we become aware of them? Antisense technology might be one solution, and despite shaky beginnings the continued commitment to research into this approach is beginning to yield results. The efforts to reduce toxicity and improve specificity and efficacy have resulted in a gene therapy approach with real promise. The potential of this approach, applied specifically to neurons, is discussed by Peter Estebeiro on pages S56–S62.It is hoped that a greater understanding of ND will lead to new therapies; however, one of the most exciting new approaches to AD treatment has resulted from the serendipitous observation that patients treated with cholesterol-biosynthesis inhibitors had a lower incidence of AD. Tobias Hartmann describes the subsequent clinical trials of these drugs as a primary therapy for AD and the highly encouraging results that have been obtained (see pages S45–S48).Although halting the progress of an ND is good, reversing the pathology of the disease is better, and after decades of research, some genuinely exciting approaches are beginning to emerge. Multiple sclerosis, a demyelinating disease that affects the peripheral nervous system (as well as the CNS) is a complex disease involving abnormal interplay between the immune and nervous systems. On pages S39–S44, Moses Rodriguez describes how it might be possible to activate selectively the endogenous repair mechanisms that stimulate remyelination.Normal and abnormal aging – is there anything we can do?There is certainly no panacea to the manifest problems of neurodegeneration, but in their fascinating article, Tom Prolla and Mark Mattson discuss the surprisingly dramatic effects observed in rats fed on a diet where the energy intake is 70% of normal (see pages S21–S31). These animals have vastly improved lifespans, retain the physiology of young animals for longer and might have increased resistance to ND; an interesting irony given the rising levels of obesity in modern society.And so I hope you will enjoy the articles in this special issue, and please remember to visit Trends in Neurosciences regularly for its continued coverage of this field and fresh insights into research advances as they occur. A recent estimate suggests that the number of people over 65 years-of-age in the USA will double between now and the year 2050. Clearly, our population is aging, and aging brings with it the increased likelihood of neurodegenerative disease (ND). As a consequence, one of the great challenges of biomedical research will be to develop successful therapeutic strategies to enable us to enjoy our old age – not just to live longer, but to live longer in health. The field of NDs is too vast to be able to cover each and every topic in this special issue, but our aim was to discuss important recent advances and highlight some of the more encouraging therapeutic approaches. Protein accumulation and potential therapeutic targetsThe most common forms of age-related NDs are Alzheimer's disease (AD) and Parkinson's disease (PD), and both are characterized by abnormal protein aggregation. AD is characterized by the formation of Aβ-containing plaques, which involves γ-secretase cleavage of a precursor protein. The identity of this enzyme is currently uncertain, but presenilins are popular candidates. On pages S2–S6, Sangram Sisodia discusses the evidence for and against presenillins, and describes how their role in the CNS is more complex than we originally thought.An important question is why these toxic proteins accumulate – why are they not eliminated? It is emerging that an overwhelmed ubiquitin-dependent proteolysis system might well be responsible, as described by Ted Dawson (pages S7–S14). The most common forms of age-related NDs are Alzheimer's disease (AD) and Parkinson's disease (PD), and both are characterized by abnormal protein aggregation. AD is characterized by the formation of Aβ-containing plaques, which involves γ-secretase cleavage of a precursor protein. The identity of this enzyme is currently uncertain, but presenilins are popular candidates. On pages S2–S6, Sangram Sisodia discusses the evidence for and against presenillins, and describes how their role in the CNS is more complex than we originally thought. An important question is why these toxic proteins accumulate – why are they not eliminated? It is emerging that an overwhelmed ubiquitin-dependent proteolysis system might well be responsible, as described by Ted Dawson (pages S7–S14). Insights from molecular analysisClearly, many NDs involve both genetic and environmental factors, and transgenic animals are one of the most widely used methods for studying genetic mutations and their pathological effects. Serge Przedborski outlines the major areas of progress resulting from the numerous animal models of Parkinson's disease, in which some of the more detailed aspects of the disease are revealed (pages S49–S55).Two other NDs for which the molecular basis is beginning to emerge are Huntington's disease (HD) and amytrophic lateral sclerosis (ALS), a progressive ND of motor neurons. HD is characterized by a CAG expansion that encodes a polyglutamine tract, which results in progressive protein accumulation. Cynthia McMurray's pioneering work in discovering the mechanism by which the CAG expansion occurs (see pages S32–S38) offers a new potential therapeutic target with implications beyond HD itself. And on pages S15–S20, Joe Beckman explains how zinc deficiency in the superoxide dismutase enzyme might underlie most, if not all, cases of ALS. Clearly, many NDs involve both genetic and environmental factors, and transgenic animals are one of the most widely used methods for studying genetic mutations and their pathological effects. Serge Przedborski outlines the major areas of progress resulting from the numerous animal models of Parkinson's disease, in which some of the more detailed aspects of the disease are revealed (pages S49–S55). Two other NDs for which the molecular basis is beginning to emerge are Huntington's disease (HD) and amytrophic lateral sclerosis (ALS), a progressive ND of motor neurons. HD is characterized by a CAG expansion that encodes a polyglutamine tract, which results in progressive protein accumulation. Cynthia McMurray's pioneering work in discovering the mechanism by which the CAG expansion occurs (see pages S32–S38) offers a new potential therapeutic target with implications beyond HD itself. And on pages S15–S20, Joe Beckman explains how zinc deficiency in the superoxide dismutase enzyme might underlie most, if not all, cases of ALS. Repair strategiesWhat is the best way to target the genetic abnormalities when we become aware of them? Antisense technology might be one solution, and despite shaky beginnings the continued commitment to research into this approach is beginning to yield results. The efforts to reduce toxicity and improve specificity and efficacy have resulted in a gene therapy approach with real promise. The potential of this approach, applied specifically to neurons, is discussed by Peter Estebeiro on pages S56–S62.It is hoped that a greater understanding of ND will lead to new therapies; however, one of the most exciting new approaches to AD treatment has resulted from the serendipitous observation that patients treated with cholesterol-biosynthesis inhibitors had a lower incidence of AD. Tobias Hartmann describes the subsequent clinical trials of these drugs as a primary therapy for AD and the highly encouraging results that have been obtained (see pages S45–S48).Although halting the progress of an ND is good, reversing the pathology of the disease is better, and after decades of research, some genuinely exciting approaches are beginning to emerge. Multiple sclerosis, a demyelinating disease that affects the peripheral nervous system (as well as the CNS) is a complex disease involving abnormal interplay between the immune and nervous systems. On pages S39–S44, Moses Rodriguez describes how it might be possible to activate selectively the endogenous repair mechanisms that stimulate remyelination. What is the best way to target the genetic abnormalities when we become aware of them? Antisense technology might be one solution, and despite shaky beginnings the continued commitment to research into this approach is beginning to yield results. The efforts to reduce toxicity and improve specificity and efficacy have resulted in a gene therapy approach with real promise. The potential of this approach, applied specifically to neurons, is discussed by Peter Estebeiro on pages S56–S62. It is hoped that a greater understanding of ND will lead to new therapies; however, one of the most exciting new approaches to AD treatment has resulted from the serendipitous observation that patients treated with cholesterol-biosynthesis inhibitors had a lower incidence of AD. Tobias Hartmann describes the subsequent clinical trials of these drugs as a primary therapy for AD and the highly encouraging results that have been obtained (see pages S45–S48). Although halting the progress of an ND is good, reversing the pathology of the disease is better, and after decades of research, some genuinely exciting approaches are beginning to emerge. Multiple sclerosis, a demyelinating disease that affects the peripheral nervous system (as well as the CNS) is a complex disease involving abnormal interplay between the immune and nervous systems. On pages S39–S44, Moses Rodriguez describes how it might be possible to activate selectively the endogenous repair mechanisms that stimulate remyelination. Normal and abnormal aging – is there anything we can do?There is certainly no panacea to the manifest problems of neurodegeneration, but in their fascinating article, Tom Prolla and Mark Mattson discuss the surprisingly dramatic effects observed in rats fed on a diet where the energy intake is 70% of normal (see pages S21–S31). These animals have vastly improved lifespans, retain the physiology of young animals for longer and might have increased resistance to ND; an interesting irony given the rising levels of obesity in modern society.And so I hope you will enjoy the articles in this special issue, and please remember to visit Trends in Neurosciences regularly for its continued coverage of this field and fresh insights into research advances as they occur. There is certainly no panacea to the manifest problems of neurodegeneration, but in their fascinating article, Tom Prolla and Mark Mattson discuss the surprisingly dramatic effects observed in rats fed on a diet where the energy intake is 70% of normal (see pages S21–S31). These animals have vastly improved lifespans, retain the physiology of young animals for longer and might have increased resistance to ND; an interesting irony given the rising levels of obesity in modern society. And so I hope you will enjoy the articles in this special issue, and please remember to visit Trends in Neurosciences regularly for its continued coverage of this field and fresh insights into research advances as they occur.