Young Perspectives for Old Diseases

Increasing knowledge in molecular and cellular biology along with improved imaging technology and surgical instruments has resulted in huge advances in cancer therapy. The understanding of several cellular signaling pathways has laid the solid foundation for the development of targeted chemotherapy, which in turn, has played critical roles in increasing the survival rates of many types of cancer during the last decade. As a consequence, molecular diagnostic tests have emerged as an important step in order to plan the most appropriate treatment strategies for each case. In this chapter, we will describe classical examples of targeted cancer therapies and illustrate how similar approaches could benefit the treatment of yet incurable neurodegenerative diseases.

Neurodegenerative disorders are an important cause of mortality and morbidity in the elderly. The most common neurodegenerative diseases are Alzheimer's disease and Parkinson's disease. Lewy body dementia is considered the third most frequent. Much less common are frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, spinocerebellar ataxias, Pick disease and prion disease. There is no therapy that is capable to avoid the progression of these disorders. Current pharmacological therapies offer symptomatic benefits with very little impact, if any, in modifying the course of these diseases. Anticholinesterase drugs are the most frequently used to treat Alzheimer's disease. Disease-modifying treatments for Alzheimer's disease are being developed. Levodopa is the most effective pharmacological treatment for Parkinson's disease but in long-term benefit declines. For this reason, association between levodopa and other forms of treatment is the best approach. There is no approved pharmacological treatment for most other forms of neurodegenerative diseases except for amyotrophic lateral sclerosis, Huntington disease and some forms of cerebellar ataxias.

Over the last decades, a large number of experimental models have been developed to explore the mechanisms underlying neurodegenerative disorders. Invertebrate models of neurodegeneration, such as the fruit fly Drosophila melanogaster and the nematode Caenorhabtidis elegans, have emerged as successful complementary systems to mammalian models, facilitating identification of relevant pathways and novel diseaseassociated genes. These organisms provide reliable systems for identifying genetic modifiers of neuropathologies and the interesting possibility of screening and testing potential drugs for treatments to prevent and/or alleviate disease symptoms.

This chapter will focus on the main experimental strategies used in Drosophila melanogaster and Caenorhabtidis elegans to study neurodegeneration. Insights from forward genetic approaches, transgenic models of human neurodegenerative disorders and studies of fly/worm homologs of human disease genes will be presented. The value of using invertebrate models for the study of neurodegeneration will be discussed, highlighting advantages and limitations associated with these studies.

All brain functions are controlled by specific synapses where the release of neurotransmitters triggers a number of signaling cascades in postsynaptic neurons. One of the most important and common events is a transient and very fast intracellular Ca²⁺ increase. Intracellular Ca²⁺ increase is fundamental for modulation of gene expression, neuronal survival and plasticity. In this chapter we will discuss the importance of Ca²⁺ in cells as well as the regulation of physiological functions in various organisms. Additionally, we will consider mechanisms used by the cells for Ca²⁺ homeostasis and for increasing intracellular Ca²⁺ concentration. Finally, the role of Ca²⁺ in neurodegenerative diseases such as Alzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), Huntington disease (HD) among others will be discussed in this chapter.

Protein misfolding is the hallmark of a large number of neurodegenerative diseases and is characterized by the presence of amyloid inclusions composed of aggregates of misfolded proteins in specific areas of the brain. The formation of those aggregates involves a multistep process that is exacerbated during periods of cellular stress. Cells have several mechanisms to regulate protein quality control that also serve as a defense line to prevent the accumulation of misfolded proteins; failures in these defenses are frequently involved in neurodegeneration. Another intriguing feature of neurodegenerative diseases, which have misfolded proteins as etiological agents, is the presence of similarities with prion diseases. Prions are unconventional infectious agents composed entirely from a misfolded form of a native protein that has the capacity to provoke and propagate to neighboring cells or even to other organisms. Nowadays, a large body of evidence has shown that most of the misfolded proteins found in degenerated brains behave as prion-like proteins, promoting misfolding and consequently, the aggregation of native protein forms which can spread to other cells or brain regions. However, unlike prion diseases, the prion-like properties of misfolded proteins are unable to naturally infect other organisms. Taken together, neurodegenerative diseases share many characteristics, of which protein misfolding is the most important. This feature has huge therapeutic implications since it raises the possibility to treat different diseases with drugs targeted to impair, block or revert protein misfolding.

Mitochondria are key organelles with a critical role as the main source of energy supply. Mitochondrial dysfunction can lead to several disorders, including neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases and the aging process. The mitochondrial respiratory chain is the main source of reactive oxygen species and because it is located in the inner mitochondrial membrane, it is also susceptible to oxidative damage, as well as other biomolecules in the vicinity, such as mitochondrial DNA. Nitric oxide is also found in the mitochondrial matrix and is involved in physiological pathways such as induction of apoptosis and generation of nitrosative stress. In this review we will discuss the complex mechanisms involved in the relationship between mitochondrial dysfunction, oxidative stress and neuronal death.

Alzheimer’s disease is the leading cause of dementia in the elderly. It is characterized by progressive memory loss and deterioration of cognitive ability, as well as by the presence of two main histopathological abnormalities in the brain: the amyloid plaques and the neurofibrillary tangles. The first is composed mainly of the aggregated form of the amyloid-beta peptide, while the latter consists of neuronal cell bodies filled with the hyperphosphorylated form of the tau protein. Although several genetic risk factors have been identified, the pathological mechanism of this disease remains elusive. As a consequence, to the present moment there is no cure to this condition or treatment capable of reliably reversing its symptoms. Hereditary forms of the disease typically have an early onset, and are predominantly associated with mutations in the molecular machinery responsible for the metabolism of a protein known as amyloidprecursor protein. In spite of the strong evidence suggesting its involvement in the pathogenesis of Alzheimer’s disease, very little of the normal physiological role of this protein or its pathway is known. A second molecular pathway involved in many cases of neurodegenerative conditions, including Alzheimer’s disease, is the cytoskeletonassociated protein tau. Tau plays an important role in biological processes like axonal transport, and much is known about the molecular mechanisms of tau dysfunction in disease. However, the precise mechanisms by which both amyloid and tau molecular signaling pathways interact in the pathology are not fully understood. As a result, the lack of a clear picture of the molecular alterations underlying this disease has represented a barrier to the development of effective treatments. In this regard, the two available options approved by the U.S. Food and Drug Administration target mostly the symptoms and provide unsatisfactory results in the long term. Many research groups in both academia and industry have focused efforts in the development of new therapies capable of reversing the cognitive impairment of patients with Alzheimer’s disease. Several of the emerging therapies had severe side effects and disappointing outcomes in terms of improving cognitive levels. However, there are some therapies that have been showing more promising results. Further studies and clinical trials are still needed to fully address the risks and benefits of new treatments in Alzheimer’s disease.

Parkinson’s disease is a complex neurodegenerative disorder, mainly characterized by the loss of dopaminergic neurons in the substantia nigra and their projections to the striatum, causing several motor deficits. Neuronal cytoplasmic inclusions, named Lewy Bodies, are found in the affected areas. Parkinson’s disease is distributed worldwide, affecting all ethnic groups and socioeconomic classes. Protein homeostasis is crucial for preventing neurodegeneration. Misfolding of proteins can lead to loss or gain of function, resulting in protein dysfunction and causing various types of diseases. Five genes containing pathogenic mutations were identified to contribute for incorrect protein conformation in Parkinson’s disease. Mitochondrial dysfunction and purinergic receptor signaling are also involved in the mechanism of disorder. Several types of pharmacological intervention were developed. Dopamine agonists are the most common therapeutic agents used currently. N-methyl-D-aspartate type glutamate receptor antagonist, monoamine oxidases and anticholinergic drugs can be therapeutic alternatives. New techniques and studies have contributed to the discovery of new genes and genetic risk factors for Parkinson’s disease. Brain banks and imaging analyses can also be very useful tools for understanding the mechanisms of disease progression. Current studies on molecular aspects of Parkinson’s disease, together with the development of new drugs, techniques and tests to improve diagnosis accuracy will bring new perspectives for PD therapies.

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion of the huntingtin protein (htt). The progressive neuronal cell loss that takes place in the caudate-putamen and neocortical regions of HD patients leads to motor, cognitive, and psychiatric function deterioration, as well as inevitable death. Although the mutated htt is pointed as the cause of HD, it is still unknown how this mutation can promote neurodegeneration. Postmortem analyses of HD patient’s brains demonstrate the presence of intracellular inclusions containing htt aggregates, which was associated to neuronal death. However, other studies suggest that inclusion formation can be neuroprotective by decreasing the levels of toxic soluble mutant htt. Moreover, many neurotransmitter systems, such as the glutamatergic, dopaminergic, endocannabinoid and trophic factor systems, are also involved in HD progression. For example, it has been demonstrated that the glutamatergic system plays an important role in the excitotoxic neuronal cell loss that takes place in HD. Despite the fact that it is clear that the main cause of HD symptoms is neuronal cell death, no therapeutic approach has yet been developed to rescue or avoid neurodegeneration. To solve this issue, a number of studies are now focusing on developing drugs that could prevent neuronal death, whereas others attempt to implement stem cells to rescue lost neurons. Both approaches have the potential to develop a disease modifying therapeutic strategy, bringing hope to HD patients.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of both upper and lower motor neurons leading to paralysis and finally to death. Non-neuronal cells, including glial cells, have been shown to actively participate in the physiopathological process occurring in ALS. Experiments using chimeric mice expressing ALS-linked mutations suggest that neighboring non-neuronal cells modulate disease phenotype. In this review, recent findings involving the role of astrocytes, microglia and of other non-neuronal cells will be discussed. The study of motor neuron microenvironment could lead to a better understanding of the physiopathology of ALS to find new pathways to slow down motor neuron degeneration.

Multiple sclerosis is a chronic, inflammatory, immune-mediated disease of the central nervous system. Current evidence indicates that a complex genetic trait associated with environmental factors probably triggers MS. The hypothesis is that the inflammatory response starts when CNS protein-specific CD4+ T cells become activated in the periphery, cross the blood/brain barrier, and induce CNS autoimmunity. A disturbed balance between cells that induce or cause demyelination and regulatory T cells capable of suppressing these auto-reactive T cells underlie MS pathogenesis. Inflammation and oxidative stress are major causes of tissue damage in the CNS. Diagnostic criteria include paraclinical laboratory assessments emphasizing the principle of lesions disseminated in time and space. Cerebrospinal fluid analysis remains mandatory in order to support the diagnosis and differentiate MS from other diseases. Disease modifying therapies (DMT) are available for MS patients like recombinant Interferon β (IFN-β) and Glatiramer Acetate (GA) that present similar clinical outcomes showing reduction in patient’s annual number of relapses, MRI T2 lesion load reduction and delay of disability. Recently, a monoclonal humanized antibody, Natalizumab, was re-launched showing a larger reduction in annual number of relapses and MRI lesions in the CNS. Besides, Fingolimod (FTY720) was also introduced as the first oral drug with similar effects. Corticosteroids are the first line therapy for acute MS exacerbations. The parenteral use of Cyclophosphamide, Mitoxantrone and Cladribine may benefit some patients with aggressive disease. Oral immunosuppressive drugs (azathioprine, mycophenolatemofetil and methotrexate) have also been reserved for patients whose disease progression cannot be controlled by DMTs.

Dementia with Lewy Bodies (DLB) and Frontotemporal Dementia (FTD) are clinically characterized mainly by gradual progressive impairment of behavior and cognitive functions. The accurate diagnosis of both disorders are very difficult due to significant overlap with other neurodegenerative symptoms. Here, in the chapter, we discuss the last.

Peripheral nerves connect the central nervous system with peripheral tissues in the body and are therefore crucial for all living animals to communicate with the environment. Due to the length of their axons, peripheral neurons are extremely vulnerable to insults. Inherited peripheral neuropathies comprise a large group of disorders characterized by progressive loss of axons or myelin that affect motor, sensory and/or autonomic nerves. Charcot-Marie-Tooth disease is the most common form of these inherited peripheral neuropathies. Peripheral nerves can also be damaged by a wide variety of stressors such as inflammation, infection, trauma, systemic disease, toxins/drugs and metabolic disturbances giving rise to several clinical subtypes of the disease. These disorders are referred to as acquired peripheral neuropathies. Ongoing research is focused on unraveling the pathogenic mechanisms underlying these debilitating diseases in order to find possible therapeutic strategies. So far, no drug therapy has been proven effective and patients have to rely on symptomatic treatments that are largely insufficient. Although there is no existing cure for peripheral neuropathies to date, some encouraging advances have been made which are also discussed in this chapter.

Increasing knowledge of the neurobiological basis of synaptic plasticity and memory has opened new venues for the development of cognitive-enhancing drugs that could be used in the treatment of memory loss associated with neurological and psychiatric disorders. Neuromodulatory systems influencing memory formation include stress hormones as well as a range of neurotransmitter and neuropeptide signaling pathways. Here, we review some of the findings on memory enhancement by drugs acting on neuromodulatory systems and discuss the possible implications for the development of cognitive enhancers.

Notwithstanding the past decades of research, efficient treatments for neurodegenerative diseases do not exist. However, stem cell therapies have become increasingly attractive options for a broad spectrum of human neurodegenerative diseases. Diverse classes of stem cells, such as embryonic stem cells (ESCs), neural stem cells (NSCs), mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) can be useful as a source material for understanding the basic biology of cellular differentiation, disease modeling, and provide novel sources for autologous cellular therapies in neurodegenerative diseases. Indeed, the transplantation of stem cells or their derivatives and the mobilization of endogenous stem cells have been proposed in animal models of neurodegenerative disease as therapeutic mechanisms to restore function. In this chapter, we discuss some general issues relating to the scientific basis of stem cell–based therapies and their prospects in neurological disorders including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and Amyotrophic lateral sclerosis.