Current Drug Targets - Volume 11, Issue 10, 2010

Over the past decades, metabolic dysfunction has emerged as one of the most common pathological condition underlying the neurodegenerative process in distinct disorders of the central and peripheral nervous system. Due to improvements in life expectancy, the world's population is ageing rapidly and the incidence of neurodegenerative diseases linked to protein misfolding and aggregation has increased and will dramatically increase over the next generations. Thus, understanding the basic mechanisms of neurodegeneration and identifying novel disease targets is urgently needed, so that new therapeutic strategies may be implemented. This review issue on ‘central and peripheral metabolic changes in neurodegenerative diseases’ revisits the fundamental concepts of bioenergetic deficits and covers the latest research-based developments on central and peripheral metabolic abnormalities in distinct neuron diseases. The theme of this review issue was inspired in the PENS Summer School on metabolic aspects of chronic brain diseases, which was held last year in Germany and involved some contributors of the present issue. Both the clinical and basic features of neurodegenerative diseases, including Alzheimer's disease, prion diseases, Huntington's disease (an autosomal dominant disease), Parkinson's disease, and motor neuron diseases, are described in this issue. Although some of these disorders have a pure genetic origin, the most common forms are sporadic, i.e., of unknown etiology. Interestingly, despite affecting selective areas in the brain, metabolic changes in peripheral cells or tissues and hypothalamic-neuroendocrine crosstalk have been also described, which may contribute for disease pathogenesis and/or constitute important biomarkers relevant for defining disease progression. Regarding the lower motor neuron diseases, which include spinal muscular atrophy, spinal bulbar muscular atrophy or Kennedy's disease (two purely genetic diseases) and amyotrophic lateral sclerosis, the muscle fibers and the neuromuscular junction have been also hypothesized as sites of crucial pathogenic events and therapeutic development. Importantly, distinct parallel pathological features may take place among the diverse group of neurodegenerative disorders, including protein aggregation, transcriptional deregulation and mitochondrial dysfunction. Although the amyloid-like fibrillary aggregates undoubtedly arise in the intracellular or extracellular milieu in many neurodegenerative diseases, the nature of pathogenic aggregate formation and the exact consequences of their accumulation are still not clear. Interestingly, ‘spreading’ of neuropathological changes linked to disease progression has been suggested to result from the intercellular transfer of these pathogenic proteins. Several mitochondrial-associated defects have been extensively researched, including oxidative stress, bioenergetic dysfunction, calcium mishandling (which may result from excitotoxic stimuli and/or stress of the endoplasmic reticulum) or intrinsic apoptosis. In some diseases the misfolded proteins have been even considered as ‘mitochondrial toxins’, since they directly interfere with the organelle. Moreover, there are some controversies concerning the evidence for classical apoptosis in many neurodegenerative diseases. Mitochondrial dysfunction has been also linked to transcription deregulation through disruption of the transcriptional co-activator peroxisome proliferator activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha). Moreover, sirtuins (NAD+-dependent protein deacetylases) have been identified to regulate the crosstalk between aging and neurodegeneration, and both PGC-1alpha and sirtuins seem to be important targets for therapeutic intervention. Indeed, these are signaling pathways induced by calorie restriction, which may have a neuroprotective and preventive role against neurodegeneration. Additionally, hypothalamic dysfunction and neuroendocrine changes governing metabolic abnormalities may be also important features in several neurodegenerative disorders. Despite increased speed of research in many neurodegenerative disorders over the last years, clinical trials focusing on metabolic strategies have yielded many disappointing results. This opened up a series of questions: i) Are metabolic changes secondary to disease onset and progression? ii) Are tested doses and/or drug protocols not well designed? iii) Are there alternative therapeutic targets that deserve more intensive research before being considered for clinical trials? and/or iv) Should we consider multiple pathological targets and thus treatment with more that one drug in future trials? Although the answers to all these questions are far from being reached, it is hoped that a greater understanding of these processes and their role(s) in disease onset and progression will lead to new treatments in the future.

Alzheimer's disease (AD) is the most common form of dementia in old age. Cognitive impairment in AD may be partially due to overall hypometabolism. Indeed, AD is characterized by an early region-specific decline in glucose utilization and by mitochondrial dysfunction, which have deleterious consequences for neurons through increased production of reactive oxygen species (ROS), ATP depletion and activation of cell death processes. In this article, we provide an overview of the alterations on energetic metabolism occurring in AD. First, we resume the evidences that link the ‘metabolic syndrome’ with increased risk for developing AD and revisit the major changes occurring on both extramitochondrial and mitochondrial metabolic pathways, as revealed by imaging studies and biochemical analysis of brain and peripheral samples obtained from AD patients. We also cover the recent findings on cellular and animal models that highlight mitochondrial dysfunction as a fundamental mechanism in AD pathogenesis. Recent evidence posits that mitochondrial abnormalities in this neurodegenerative disorder are associated with changes in mitochondrial dynamics and can be induced by amyloid-beta (Aβ) that progressively accumulates within this organelle, acting as a direct toxin. Furthermore, Aβ induces activation of glutamate N-methyl-D-aspartate receptors (NMDARs) and/or excessive release of calcium from endoplasmic reticulum (ER) that may underlie mitochondrial calcium dyshomeostasis thereby disturbing organelle functioning and, ultimately, damaging neurons. Throughout the review, we further discuss several therapeutic strategies aimed to restore neuronal metabolic function in cellular and animal models of AD, some of which have reached the stage of clinical trials.

Prion diseases are fatal neurodegenerative disorders that affect humans and other mammals. The hallmark of these diseases is the conformational change of the cellular prion protein (PrPC) to the misfolded protein capable of propagation and associated with neurodegeneration, named prion (PrPSc). In a strict sense, prion diseases are a consequence of aberrations in the metabolism of the cellular prion protein (PrPC). This brief review addresses current understanding of metabolic disturbances in prion disorders at the cellular, organ and organism level, selectively pointing out some relevant diagnostic and treatment options.

Huntington's disease (HD) is a genetic neurodegenerative disease selectively leading to striatal neurodegeneration, but also affecting the cortex and the hypothalamus. Although it is hard to predict the sequence of celldamaging events occurring in HD patients, several pathological mechanisms have been proposed to explain HD selective neurodegeneration and disease symptomatology. Abnormalities in mitochondrial function and bioenergetics contribute to cell death and have been reported in HD-affected individuals, both in central and peripheral tissues. Moreover, the latter has been characterized in several HD models. Thus, this review describes the converging mechanisms that lead to mitochondrial and metabolic abnormalities in thoroughly studied in vivo and in vitro HD models, including excitotoxicity, altered calcium handling, changes in mitochondrial structure and dynamics and transcription deregulation, which may represent important disease therapeutic targets. Furthermore, the review describes the current evidences of metabolic disturbances in the brain of HD-affected humans and of peripheral metabolic and mitochondrial changes, weight loss and endocrine abnormalities operating in the whole HD body.

Huntington's disease (HD) is neither a fatal hereditary neurodegenerative disorder without satisfactory treatments nor a cure. It is caused by a CAG repeat expansion in the huntingtin gene. The clinical symptoms involve motor-, cognitive- and psychiatric disturbances. Recent studies have shown that non-motor symptoms and signs, such as mood changes, sleep disturbances and metabolic alterations often occur before the onset of overt motor impairments. The hypothalamus is one of the main regulators of emotion, sleep and metabolism, and it is therefore possible that dysfunction of the hypothalamus and neuroendocrine circuits may, at least partly, be responsible for these non-motor symptoms in HD. Several hypothalamic and neuroendocrine changes have now been identified in clinical HD as well as in rodent models of the disease. These changes could be important both in the pathogenesis of HD, constitute biomarkers to track disease progression as well as to provide novel therapeutic targets for this devastating disease. The current state of knowledge in the area of hypothalamic and neuroendocrine changes in both patients and rodent models of HD is summarized in this review, and their potential as targets for novel treatment paradigms are discussed.

Lower motor neuron (LMN) degeneration occurs in several diseases that affect patients from neonates to elderly and can either be genetically transmitted or occur sporadically. Among diseases involving LMN degeneration, spinal muscular atrophy (SMA) and spinal bulbar muscular atrophy (Kennedy's disease, SBMA) are pure genetic diseases linked to loss of the SMN gene (SMA) or expansion of a polyglutamine tract in the androgen receptor gene (SBMA) while amyotrophic lateral sclerosis (ALS) can either be of genetic origin or occur sporadically. In this review, our aim is to put forward the hypothesis that muscle fiber atrophy and weakness might not be a simple collateral damage of LMN degeneration, but instead that muscle fibers may be the site of crucial pathogenic events in these diseases. In SMA, the SMN gene was shown to be required for muscle structure and strength as well as for neuromuscular junction formation, and a subset of SMA patients develop myopathic pathology. In SBMA, the occurence of myopathic histopathology in patients and animal models, along with neuromuscular phenotype of animal models expressing the androgen receptor in muscle only has lead to the proposal that SBMA may indeed be a muscle disease. Lastly, in ALS, at least part of the phenotype might be explained by pathogenic events occuring in skeletal muscle. Apart from its potential pathogenic role, skeletal muscle pathophysiological events might be a target for treatments and/or be a preferential route for targeting motor neurons.

Mitochondrial dysfunction is a common hallmark of ageing-related diseases involving neurodegeneration. Huntington's disease (HD) is one of the most common monogenetic forms of neurodegenerative disorders and shares many salient features with the major sporadic disease of neurodegeneration, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD). Recent evidence from the study of transgenic and knockout animal models of HD has stimulated new perspectives on mitochondrial dysfunction in HD and possibly other neurodegenerative diseases. The transcriptional co-activator PGC-1a, originally described as a metabolic master regulator in peripheral tissues such as brown adipose tissue (BAT) and muscle, has emerged as a molecular link between transcriptional dysregulation and mitochondrial dysfunction in the brain. PGC-1α knockout mice display many phenotypic similarities to transgenic mouse models of HD and the gene-expression analysis of tissues from HD patients revealed a disruption of the PGC-1α regulatory pathway. Hence, mitochondrial and transcriptional dysregulation in HD - previously thought to be unrelated mechanisms of neurodegeneration - appear to be directly linked at the molecular level. The clinical and therapeutic potential of targeting the PGC-1α in HD is further highlighted by the finding that common genetic variations in the PGC-1α gene significantly modify the disease onset, delaying the onset of motor symptoms by several years. The present review provides an overview of the advances in the understanding of the role of the PGC-1a system in HD pathogenesis and explores the implications for ALS, AD and PD.

Aging has been a subject of interest since primordial times. More recently, it became clear that aging is the major known risk factor for several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease. A major focus in the field of aging is to examine whether the genetic regulators of lifespan also regulate the trigger and/or progression of age-related disorders. Sirtuins, which belong to the Sir2 family of NAD+-dependent deacetylases, are known to regulate longevity in yeast, worms, and flies. In mammals, there are seven homologs of the yeast Sir2, Sirt1-7. Therefore, the challenge now is to unravel howthe seven mammalian Sir2 proteins communicate to regulate the cross talk between aging and the onset and progression of age-related disorders. Here, we review how sirtuins contribute for aging and, in particular, for neurodegeneration and how they are becoming attractive targets for therapeutic intervention.

It is well known that calorie restriction (CR) can retard the aging process in organisms ranging from yeast to non-human primates, and delay the onset of numerous age-related diseases including neurodegenerative disorders. Translation of the knowledge gained from CR research in animal models to disease prevention strategies in humans should provide therapeutic approaches for these diseases. Signaling pathways induced by CR are therefore potentially new therapeutic targets for neurodegenerative diseases. This review summarizes the evidence on key biological mechanisms underlying the beneficial effects of CR based on our current understanding, with particular emphasis on the recent impact of CR on neuroprotection, and on the emerging development of pharmacological agents that target signaling pathways induced by CR. We focus in particular on recent findings on sirtuins for prevention of neurodegenerative diseases.

Cancer is caused by alterations in oncogenes, onco-suppressor genes and micro-RNA genes. These alterations are either genetic or epigenetic. Most genetic lesions of cancer are acquired, somatic events, although germ-line mutations can predispose to heritable or familial cancers. Cancer cells accumulate several genetic alterations, including chromosomal abnormalities and mutations in the nucleotide sequence of DNA. Using massively parallel sequencing technologies, tens of thousands of somatic mutations have been identified in cancer cell genome, hundreds of which in coding exons, along with tens of genomic rearrangements. Driver mutations, which provide a selectable fitness advantage to the cell and facilitate its clonal expansion, are estimated to be tens in different tumor types [1-5]. The most fundamental conclusion from DNA sequencing of cancer cells is that the cancer genome is composed of a larger number of infrequently mutated genes, each providing a small fitness advantage, and few commonly mutated genes. Despite the fact that a small number of these genes are mutated in a high proportion of cancers, the prevalence at which the majority are mutated within different tumors of the same cancer type is low. These results are not in accord with the classical paradigm, in which a small number of key genes, mutated in a linear temporal sequence, drive tumorigenesis [1-2]. DNA is continuously assaulted by a variety of endogenous (e.g. reactive radicals) and exogenous (e.g. radiations and carcinogens) agents that damage DNA. DNA lesions induced by these agents are normally repaired by an elaborated network of DNA repair pathways. Cancer cells frequently harbor defects in DNA repair pathways, leading to genetic instability that in turn, at least in part, contributes to generate the thousands of genetic alterations found in cancer cells. Attempts to uncover the molecular mechanisms underlying genetic instability in cancer cells have shown that there are at least two forms of genetic instability. Loss of mismatch repair (MMR) enzymes leads to random acquisition of somatic mutations throughout the genome (microsatellite instability, MIN) [6]. Defects of proteins involved in mitotic regulation lead to an increased rate of gain and/or loss of chromosome or portions thereof (chromosome instability, CIN) and aneuploidy [7]. Almost all cancer cells are genetically unstable [8] and chronic inflammation, as one of the most recognized risk factor for many cancers, induces, by a variety of direct and indirect mechanisms, genetic instability [9]. Genetic instability serves as the engine of tumor progression by random activation of oncogenes and inactivation of onco-suppressors. Genetic diversification induced by genetic instability bestows a growth advantage upon the cancer cells enabling them to clonally expand in a Darwinian somatic evolutionary process [10]. Acquisition of mutations in oncogenes and tumor suppressor genes, and in additional genes that normally function in maintaining genomic integrity, perpetuate genetic instability [8], which is itself subject to natural selection. Cells with too little genetic instability may die by insufficient adaptability whereas cells with too much genetic instability may die by genetic catastrophe. Genetic instability accounts for the most striking and clinically relevant features of cancer, namely genotypic and, as a consequence, phenotypic (and thus clinical) intertumor and intratumor heterogeneity of cancer cells, including acquisition of resistance to therapy. No two tumors are genetically and phenotipically alike and no single tumor is composed of genetically identical cells, with each cell having a unique mutational signature [11]. Although representing a specific and defining hallmark of cancer cells [8], genetic instability still remains an as-yet unexplored therapeutic target. The aim of this monographic issue entitled “Targeting genetic instability and anti-cancer strategy” is to collect contributions outlining the concept of targeting genetic instability (and molecular mechanisms thereof) as a truly innovative approach that specifically kills cancer cells with unstable genome while leaving unaffected normal, genetically stable normal cells with intact DNA repair systems.......

Normal human cells replicate their DNA with exceptional accuracy. It has been estimated that approximately one error occurs during DNA replication for each 109 to 1010 nucleotides polymerized. In contrast, malignant cells exhibit multiple chromosomal abnormalities and contain tens of thousands of alterations in the nucleotide sequence of nuclear DNA. To account for the disparity between the rarity of mutations in normal cells and the large numbers of mutations present in cancer, we have hypothesized that during tumor development, cancer cells exhibit a mutator phenotype. As a defining feature of cancer, the mutator phenotype remains an as-yet unexplored therapeutic target: by reducing the rate at which mutations accumulate it may be possible to significantly delay tumor development; conversely, the large number of mutations in cancer may make cancer cells more sensitive to cell killing by increasing the mutation rate. Here we summarize the evidence for the mutator phenotype hypothesis in cancer and explore how the increased frequency of random mutations during the evolution of human tumors provides new approaches for the design of cancer chemotherapy.

Based on the gene and pathway centric concept of cancer, current approaches to cancer drug treatment have been focused on key molecular targets specific and essential for cancer progression and drug resistance. This approach appears promising in many experimental models but unfortunately has not worked well in the vast majority of cancers in clinical settings. Many new proposals, based on the same rationale of identifying a “magic bullet” are emerging now that target the epigenetic level as well as some other new targets including metabolic regulation, genetic instability and tumor environments. In spite of the optimism resulting from these new approaches there is still a key challenge that remains regarding cancer drug therapy in the form of multiple levels of genetic and epigenetic heterogeneity. Using the recently formulated genome theory, the importance of bio-heterogeneity and its complex relationships between different levels has been discussed and in particular, the concept and methods used to monitor and target genome level heterogeneity. By briefly mentioning some newly introduced treatment options, this review further discusses the common challenges for the field as well as possible future directions of research.

One of the main reasons why most patients with advanced cancer are not curable with the therapies available is the broad heterogeneity of cancer cells, inherently related to their genomic instability that reflects defects of cell cycle checkpoints and DNA mismatch repair (MMR). The present paper reviews today's knowledge of MMR. Microsatellite (DNA repetitive sequences) instability (MSI) used as a surrogate marker of MMR defects was associated with a predisposition to somatic mutations of several genes including those involved in the neoplastic transformation and tumor progression. Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by germ line mutation in genes involved in MMR such as hMLH1 or hMLH2, or less frequently hMLH6 or hPMS2; it is associated with a high risk of intestinal cancer (CRC) and other tumors including endometrial, stomach, kidney and brain. There is ample preclinical evidence that cells deficient in MMR are resistant to methylating agents and to some antimetabolites, including 5FU, which is the drug used most for the CRC, whereas they are equally sensitive to oxaliplatin and possibly more sensitive to irinotecan. More studies are needed on the importance of MMR for sensitivity to different anticancer regimens and drugs, so this knowledge can guide rational therapy according to the tumor MMR status.

Aneuploidy is one of the major hallmarks of cancer cells and several paths towards aneuploidy have been described. However, the relevance for tumor initiation or progression and how tumors deal with the initial aneuploidy related stress response is still unclear and recent results suggest that aneuploidy can even have tumor suppressive effects under certain conditions. The molecular mechanisms leading to and sustaining growth of aneuploid cells are just at the beginning to be understood and might provide new targets for cancer drug development. We will discuss some of the ideas to specifically kill aneuploid cells by targeting key regulators of mitosis.

During the process of tumorigenesis, certain cancers are known to develop deficiencies in one or more major pathways of DNA damage repair, rendering them critically dependent on alternative repair processes for maintaining genomic integrity and viability. Targeting these alternative DNA repair mechanisms is a potentially highly-specific anticancer strategy, as their inhibition is theoretically toxic only to tumor cells and not to normal tissues. We will review here the rationale behind this strategy and provide examples of its application. We will also discuss several as yet unanswered questions surrounding this strategy, including whether human cancers frequently harbor synthetically lethal interactions in DNA repair and, if so, how patients might be identified who would benefit from targeting such interactions.

Multiple karyotypic abnormalities and chromosomal instability are characteristic features of many cancers that are relatively resistant to chemotherapeutic agents currently used in the clinic. These same features represent potentially targetable “states” that are essentially tumor specific. The assessment of the chromosomal state of a cancer cell population may provide a guide for the selection or development of drugs active against aggressive and intractable cancers.