CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 9, Issue 3, 2010

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized pathologically by the presence of extracellular senile plaques and intracellular neurofibrillary tangles. The main protein components of senile plaques are amyloid-β peptides (Aβ), secreted proteolytic derivatives of the amyloid precursor protein (APP). Excessive synaptic loss is thought to be one of the earliest events in AD, and synaptic loss is an excellent correlate with memory loss. Aβ oligomers bind to synaptic sites and remove dendritic spines. Consistent with these structural abnormalities, over-expression of APP leads to Aβ secretion and loss of spines on neurons overproducing APP that phenocopies quantitatively the effects of oligomeric Aβ addition at concentrations reached in the brains of individuals with AD; these neurons also show depressed glutamatergic transmission. Given the memory deficits observed in AD, it is notable that soluble Aβ oligomers impair long-term potentiation (a synaptic model of memory) and memory, which can be ameliorated by treatment with antibodies to Aβ or small molecules that inhibit Aβ aggregation. However, the subcellular source (pre- vs postsynaptic compartments) of Aβ, as well as the mechanisms of its production and actions that lead to synaptic loss, remain poorly understood. For example, it is not known if increased Aβ production in one neuron will affect structural plasticity in a nearby neuron. To better understand the interaction between Aβ and synaptic function, Wei and colleagues sought to identify the subcellular sites from which Aβ acts. APP and its derivatives, as well as components of the APP-processing enzymes β- and γ-secretase, have been detected in axons and dendrites. However, detecting effects originating from axonally or dendritically produced Aβ has been challenging. Wei et al. reasoned that if Aβ overproduction could cause spine loss in APP-over-expressing neurons, then neighboring neurons close to Aβ-containing structures may also be exposed to higher levels of secreted Aβ and therefore lose their spines. The authors isolated the sites of increased Aβ production by selectively expressing APP in pre- or postsynaptic neurons, and then used two-photon laser-scanning imaging to monitor the synaptic deficits caused by such dendritic or axonal Aβ. They found that either dendritic or axonal Aβ overproduction was sufficient to cause local spine loss and compromise plasticity in the nearby dendrites of neurons that did not express Aβ. The production of Aβ and its effects on spines were sensitive to blockade of action potentials or nicotinic receptors; the effects of Aβ (but not its production) were sensitive to N-methyl-D-aspartate receptor blockade. These findings indicate that continuous overproduction of Aβ at dendrites or axons acts locally to reduce the number and plasticity of synapses. One caveat in the study of Wei et al. is that acute production or delivery of Aβ was employed, and the effects observed may not be entirely representative of events that occur in a chronic condition such as AD. Nevertheless, the observed effects in spine reduction were similar in magnitude and pharmacological sensitivity to effects produced by concentrations of Aβ estimated to occur in AD brain. It is possible that production of Aβ in axons or dendrites leads to secretion of additional toxic agents or prevents normal synaptic function and thereby leads to the local effects observed. Identifying the local target(s) of Aβ that leads to reduction of spines and their plasticity will be crucial to elucidating the mediators of these synaptic effects, and possibly the development of new therapeutic strategies.

These past years have seen the publication of numerous scientific articles and books on amyotrophic lateral sclerosis (ALS) that probably reflect the great human and social impact of this devastating disease on affected patients and relatives. It is common to define ALS as a “treatable”, although “far from being curable”, disorder. Multidisciplinary teams in specialized ALS centers are looking to identify reliable pathogenic markers of the disease, both in familial and sporadic cases, in attempts to design effective therapies capable of slowing down the loss of cortical, brainstem, and spinal cord motor neurons. This “Hot Topic” issue entitled “Neuroprotection in Amyotrophic Lateral Sclerosis: From Pathology to Treatment”, edited by Gabriele Siciliano and Francesco Fornai and focused on a recent ad hoc meeting held in Pisa in September 2009, gathers the most recent knowledge on a fundamental topic that has been the target of a number of basic and applied research strategies in the last decade. This issue comprehensively covers the main aspects related to the mechanisms and pathways leading to neurodegeneration in ALS, while the contributing authors clearly track possible developments of the more recent experimental acquisitions in terms of planning therapeutic approaches that could be valuable for a pathogenic treatment of this disease. Topics such as experimental models of ALS, cell culture and animal models, and mechanisms of motor neuron degeneration such as autophagy, histone deacetylation, protein aggregation and defective RNA metabolism, glutamate excitotoxicity and oxidative stress, are treated in a perspective which seeks to report what significantly can be translated from basic research to promising clinical application, ranging from neuro-protective drugs to stem cell therapy. The establishment of a relationship between “a factor and the disease” can be an important step in unraveling some of ALS's mystery and might be utilized to develop more appropriate experimental designs and targeted clinical trials.

Amyotrophic lateral sclerosis (ALS) is a difficult disease to study as it is mostly sporadic and rapidly progressive. Identification of genes causing familial ALS (FALS) has been instrumental in advancing our understanding of ALS pathogenesis, most notably with the use of mutant superoxide dismutase 1 (SOD1) models of disease. For 15 years SOD1 models have been the backbone of ALS research, but no effective treatments have been developed. However, recent advances have been made in the genetics of ALS with the identification of mutations in TAR DNA binding protein (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS), both of which have roles in RNA-processing and gene expression. Molecular links between ALS and frontotemporal dementia (FTD) are also suggested by linkage of ALS-FTD to chromosome 9. The study of the genetics of sporadic ALS (SALS) has been less fruitful, although this may change as we enter the era of resequencing. Further important clues as to the causes of ALS will come from the identification of other gene mutations that cause FALS, variants that increase susceptibility to SALS, and genetic factors that modify the ALS phenotype.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by loss of motor neurons both in the brain and spinal cord, which dramatically reduces life expectancy. ALS occurs either in familial ALS or, more frequently, in sporadic ALS forms. Several mechanisms have been postulated to underlie motor neuron death. In the present paper, starting from some of the genes related to familial ALS, we overview and discuss their potential role in modifying of the physiological clearance of altered proteins and organelles in motor neurons. Special emphasis is placed on the role of autophagy, which seems to prevail as a protein clearing system over other multienzymatic pathways such as the proteasome within motor neurons. The evidence which links an altered autophagy to the onset of motor neuron death proposes that this biochemical pathway might represent a final common mechanism underlying both inherited and sporadic forms of ALS. In light of these findings we also analyze the potential significance of a novel association between ALS, altered autophagy, and mutations of nuclear proteins such as TAR-DNA-Binding Protein 43 and fused in sarcoma/translated in liposarcoma. Such an association appears to be critical since it is now well demonstrated that all sporadic and most familiar forms of ALS are characterized by altered deposition and mislocalization of TAR-DNA-Binding Protein 43. These novel insights into the pathogenesis of ALS may lead to the identification of novel strategies to promote motor neuron survival.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with progressive muscular wasting and paralysis due to loss of motor neurons in the primary motor cortex, brainstem and spinal cord. Alterations of transcriptional activity due to an unbalance of the activity of histone acetyl transferases (HAT) and histone deacetylases (HDACs) have been described in a variety of neurodegenerative conditions in vitro and in vivo. HDACs can be grouped into four different classes with distinct cellular localization and functions. HDAC inhibitors have recently been discovered as potential neuroprotective drugs for the treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). A major limitation, however, lies in the broad spectrum of action of currently available HDAC inhibitors causing a variety of toxic side effects.

The presence of protein inclusions within the central nervous system is a characteristic of most neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Aggregates may induce cell death trough several mechanisms, such as sequestration of essential cellular components, clogging of the proteasome system, and/or disruption of axonal transport. The neuropathological signature of ALS is represented by the presence of ubiquitinated inclusions immunoreactive for the protein TDP-43 in the cytoplasm of motor neurons. Recent studies demonstrated that a significant percentage of familial ALS cases are caused by pathogenic mutations in the TAR DNA binding protein and fused in sarcoma/translocated in liposarcoma genes encoding, respectively, for TDP-43 and FUS proteins. Both TDP-43 and FUS are DNA/RNA-binding proteins involved in transcriptional regulation and splicing, shuttling, maturation and transport of mRNA molecules. Mutations in the two genes seem to induce a nucleo-cytoplasmic redistribution of FUS and TDP-43, possibly promoting aggregate formation and/or disrupting their physiological nuclear functions or their interactions with specific RNA targets. Those findings collectively suggest that alterations in cellular RNA metabolism may trigger motor neuron degeneration.

Glutamate-induced excitotoxicity is responsible for neuronal death in acute neurological conditions as well as in chronic neurodegeneration. In this review, we give an overview of the contribution of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis (ALS). The selective motor neuron death that is the hallmark of this neurodegenerative disease seems to be related to a number of intrinsic characteristics of these neurons. Most of these characteristics relate to calcium entry and calcium handling in the motor neurons as intracellular free calcium concentrations increase quickly due to a high glutamate-induced calcium influx in combination with a low calcium-buffering capacity. The high calcium influx is because of the presence of GluR2 lacking, calcium-permeable AMPA receptors while a low expression of calcium-binding proteins explains the low calcium-buffering capacity. In the absence of these proteins, mitochondria play an important role to remove calcium from the cytoplasm. While all of these characteristics make at least a subpopulation of motor neurons intrinsically very prone to AMPA receptor mediated excitotoxicity, this vulnerability is further increased by the disease process. Mutated genes as well as unknown factors do not only influence the intrinsic characteristics of the motor neurons, but also the properties of the surrounding astrocytes. In conclusion, excitotoxicity remains an intriguing pathological pathway that could not only explain the selectivity of the motor neuron death but also the role of surrounding non-neuronal cells in ALS. In addition, excitotoxicity is also an interesting drug-able target as indicated by the only FDA-approved drug, riluzole, as well as by a number of ongoing clinical trials.

Owing to uncertainty on the pathogenic mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) riluzole remains the only available therapy, with only marginal effects on disease survival. Here we review some of the recent advances in the search for disease-modifying drugs for ALS based on their putative neuroprotective effetcs. A number of more or less established agents have recently been investigated also in ALS for their potential role in neuroprotection and relying on antiglutamatergic, antioxidant or antiapoptotic strategies. Among them Talampanel, beta-lactam antibiotics, Coenzyme Q10, and minocycline have been investigated. Progress has also been made in exploiting growth factors for the treatment of ALS, partly due to advances in developing effective delivery systems to the central nervous system. A number of new therapies have also been identified, including a novel class of compounds, such as heat-shock protein co-inducers, which upregulate cell stress responses, and agents promoting autophagy and mitochondriogenesis, such as lithium and rapamycin. More recently, alterations of mRNA processing were described as a pathogenic mechanism in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations. This knowledge is expected to improve our understanding of the pathogenetic mechanism in ALS and developing more effective therapies.

Given the lack of effective drug treatments for amyotrophic lateral sclerosis (ALS), compelling preclinical data on stem cell research has targeted this disease as a candidate for stem cell treatment. Stem cell transplantation has been effective in several animal models, but the underlying biological pathways of restorative processes are still unresolved. Several mechanisms such as cell fusion, neurotrophic factor release, endogenous stem cell proliferation, and transdifferentiation may explain positive therapeutic results in preclinical animal models, in addition to replacement of lost motor neurons. The clinical target in ALS has shifted from being neuroncentered to focus on the interaction between motor neurons and non-neuronal cells (mainly astroglial or microglial). In fact, one of the fundamental unanswered questions in ALS is whether and how much motor neuron death depends on neighboring cells, and how wildtype non-neuronal cells may protect motor neurons expressing an ALS-causing mutation. Lately, motor neuron replacement has been successfully achieved in animal models with reinnervation of the muscle target. Even if many biological issues need to be solved in preclinical models, preliminary stem cell transplantation trials have been performed in ALS patients with conflicting results. The review discusses relevant topics regarding the application of stem cell research to ALS focusing on their therapeutic relevance and mechanisms of action.

The immune system has been found to be involved with positive and negative effects in the nervous system of amyotrophic lateral sclerosis (ALS) patients. In general, T cells, B cells, NK cells, mast cells, macrophages, dendritic cells, microglia, antibodies, complement and cytokines participate in limiting damage. Several mechanisms of action, such as production of neurotrophic growth factors and interaction with neurons and glial cells, have been shown to preserve these latter from injury and stimulate growth and repair. The immune system also participates in proliferation of neural progenitor stem cells and their migration to sites of injury and this activity has been documented in various neurologic disorders including traumatic injury, ischemic and hemorrhagic stroke, multiple sclerosis, infection, and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease and ALS). Many therapies have been shown to stimulate the protective and regenerative aspects of the immune system in humans, such as intravenous immunoglobulins, and other experimental interventions such as vaccination, minocycline, antibodies and neural stem cells, have shown promise in animal models of ALS. Consequently, several immunosuppressive and immunomodulatory therapies have been tried in ALS, generally with no success, in particular intravenous immunoglobulins. The multiple aspects of the immune response in ALS are beginning to be appreciated, and their potential as pharmacologic targets in neurologic disease is being explored.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting upper and lower motor neurons characterized by progressive weakness, respiratory failure and death within 3-5 years. It has been proposed that glutamate-related excitotoxicity may promote motor neuron death in ALS. Glutamatergic circuits of the human motor cortex can be activated noninvasively using transcranial magnetic stimulation (TMS) of the brain, and repetitive TMS (rTMS) can produce changes in neurotransmission that outlast the period of stimulation. In recent years a remarkable number of papers about the potential effects of rTMS in several neurological disorders including ALS has been published. Preliminary studies have shown that rTMS of the motor cortex, at frequencies that decrease cortical excitability, causes a slight slowing in the progression rate of ALS, suggesting that these effects might be related to a diminution of glutamate-driven excitotoxicity. RTMS could also interfere with motor neuron death through different mechanisms: rTMS could modulate the production of brain-derived neurotrophic factor (BDNF), a potent survival factor for neurons, that in turn might represent a promoter of motor neuron sparing in ALS. Despite some promising preliminary data, recent studies have demonstrated a lack of significant long-term beneficial effects of rTMS on neurological deterioration in ALS. However, further studies are warranted to evaluate the potential efficacy of different protocols of motor cortex stimulation (in terms of technique, duration and frequency of stimulation), particularly during the early stages of the disease when the progression rate is more pronounced.

Medulloblastoma is the most common malignant brain tumor in children. This malignant tumor of the cerebellum commonly affects children and is believed to arise from the precursor cells of the external granule layer or neuroepithelial cells from the cerebellar ventricular zone of the developing cerebellum. The standard treatment, consisting of surgery, craniospinal radiotherapy and chemotherapy, still provides a poor overall survival for infants and young children. Furthermore, the dose of radiation that can be safely given without causing extensive neurocognitive and endocrinologic sequelae is limited. Therefore, understanding the oncogenic pathways that lead to medulloblastoma, as well as the identification of specific molecular targets with significant therapeutic implications in order to develop new strategies for therapy, is crucial to improve patient survival without substantially increasing toxicity. In this review, we discuss recent therapeutics for treating medulloblastoma, focusing on new molecular targets, as well as advances in translational studies for the treatment of this malignancy.

Parkinsons'disease (PD) is a common neurodegenerative disorder characterized by the presence of tremor, muscle rigidity, slowness of voluntary movements and postural instability. One of the pathological hallmarks of PD is loss of dopaminergic (DAergic) neurons in the subtantia nigra pars compacta (SNpc). The cause and mechanisms underlying the demise of nigrostriatal DAergic neurons are not fully understood, but interactions between genes and environmental factors are recognized to play a critical role in modulating the vulnerability to PD. Current evidence points to reactive glia as a pivotal factor in PD, but whether astroglia activation may protect or exacerbate DAergic neuron loss is the subject of much debate. Astrocytes and microglia are the key players in neuroinflammatory responses, secreting an array of pro- and anti-inflammatory cytokines, anti-oxidants and neurotrophic factors. These mediators act as double-edged swords, exerting both detrimental and neuroprotective effects. Here, the contribution of astrocytes and microglia in mediating the effects of both genetic and environmental factors, including hormones, endotoxins and neurotoxins, and their ability to influence DAergic neurodegeneration, neuroprotection and neurorepair will be discussed. Approaches capable to regulate glial-associated oxidative stress and mitochondrial damage, by decreasing inflammatory burden, restoring mitochondrial function and DAergic neuron metabolism, might hold great promise for therapeutic interventions. Therapies that support astrocyte function, replacing astrocytes either modified or unmodified in culture, may represent novel approaches targeting astrocytes to promote DAergic neurorescue. Dissecting the molecular determinants of glia-neuron crosstalk will give us the possibility to test novel strategies to promote restoration of injured nigrostriatal DAergic neurons.

The glutamate/cystine antiporter system xc¯ transports cystine into cells in exchange for the important neurotransmitter glutamate at a ratio of 1:1. It is composed of a specific light chain, xCT, and a heavy chain, 4F2, linked by a disulfide bridge. Both subunits are localized prominently in the mouse and human brain especially in border areas between the brain and periphery including vascular endothelial cells, ependymal cells, choroid plexus, and leptomeninges. Glutamate exported by system xc¯ is largely responsible for the extracellular glutamate concentration in the brain, whereas the imported cystine is required for the synthesis of the major endogenous antioxidant, glutathione. System xc¯ thus connects the antioxidant defense with neurotransmission and behavior. Disturbances in the function of system xc¯ have been implicated in nerve cell death due to increased extracellular glutamate and reduced intracellular glutathione. In vitro, inhibition of cystine import through system xc¯ leads to cell death by a mechanism called oxidative glutamate toxicity or oxytosis, which includes depletion of intracellular glutathione, activation of 12-lipoxygenase, accumulation of intracellular peroxides, and the activation of a cyclic guanosine monophosphate (cGMP)-dependent calcium channel towards the end of the death cascade. Cell death caused by oxytosis is distinct from classical apoptosis. In this contribution, we discuss the function of system xc¯ in vitro and in vivo, the role of xCT as an important but due to its dual role probably ambivalent drug target, and the relevance of oxytosis as an in vitro assay for the identification of novel neuroprotective proteins and signaling pathways.