Contribution of RNA/DNA Binding Protein Dysfunction in Oligodendrocytes in the Pathogenesis of the Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration Spectrum Diseases.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two incurable neurodegenerative disorders, often considered as the extreme manifestations of a disease spectrum, as they share similar pathomechanisms. In support of this, pathological aggregation of the RNA/DNA binding proteins trans-activation response element DNA-binding protein 43 (TDP-43) or fused in sarcoma (FUS) is the pathological hallmark found in neurons and glial cells of subsets of patients affected by either condition (i.e.

Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders.

Neurodegenerative diseases are a heterogeneous group of disorders whose incidence is likely to duplicate in the next 30 years along with the progressive aging of the western population. Non-cell-specific therapeutics or therapeutics designed to tackle aberrant pathways within neurons failed to slow down or halt neurodegeneration. Yet, in the last few years, our knowledge of the importance of glial cells to maintain the central nervous system homeostasis in health conditions has increased exponentially, along with our awareness of their fundamental and multifaced role in pathological conditions.

Fucosylated ubiquitin and orthogonally glycosylated mutant A28C: conceptually new ligands for lectin (BambL).

Two orthogonal, metal free click reactions, enabled to glycosylate ubiquitin and its mutant A28C forming two protein scaffolds with high affinity for BambL, a lectin from the human pathogen . A new fucoside analogue, with high affinity with BambL, firstly synthetized and co-crystallized with the protein target, provided the insights for sugar determinants grafting onto ubiquitin. Three ubiquitin-based glycosides were thus assembled.

Astrocytes in Motor Neuron Diseases.

Motor neuron disorders are highly debilitating and mostly fatal conditions for which only limited therapeutic options are available. To overcome this limitation and develop more effective therapeutic strategies, it is critical to discover the pathogenic mechanisms that trigger and sustain motor neuron degeneration with the greatest accuracy and detail. In the case of Amyotrophic Lateral Sclerosis (ALS), several genes have been associated with familial forms of the disease, whilst the vast majority of cases develop sporadically and no defined cause can be held responsible.

Astrocytes: Emerging Therapeutic Targets in Neurological Disorders.

Astrocytes fulfil several functions that collectively contribute to maintain the optimal microenvironment for neuronal function and survival. The multiplicity and complexity of these activities clearly indicates that the correct performance of astrocytes is crucial for the physiological functioning of the nervous system, and its derangement may contribute to the occurrence and progression of many neurological disorders. Although rectifying astrocyte malfunction has successfully counteracted disease pathogenesis and outcome in many preclinical settings, the translation of this revolutionary approach into clinical practice urges the development of innovative, safe, and effective systems for both the selective delivery of therapeutics to the astrocytes and astrocyte replacement strategies.

Disruption of the astrocytic TNFR1-GDNF axis accelerates motor neuron degeneration and disease progression in amyotrophic lateral sclerosis.

Considerable evidence indicates that neurodegeneration in amyotrophic lateral sclerosis (ALS) can be conditioned by a deleterious interplay between motor neurons and astrocytes. Astrocytes are the major glial component in the central nervous system (CNS) and fulfill several activities that are essential to preserve CNS homeostasis. In physiological and pathological conditions, astrocytes secrete a wide range of factors by which they exert multimodal influences on their cellular neighbours.

Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo.

GLE1 mutations cause lethal congenital contracture syndrome 1 (LCCS1), a severe autosomal recessive fetal motor neuron disease, and more recently have been associated with amyotrophic lateral sclerosis (ALS). The gene encodes a highly conserved protein with an essential role in mRNA export. The mechanism linking Gle1 function to motor neuron degeneration in humans has not been elucidated, but increasing evidence implicates abnormal RNA processing as a key event in the pathogenesis of several motor neuron diseases.

PTEN depletion decreases disease severity and modestly prolongs survival in a mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is the second most common genetic cause of death in childhood. However, no effective treatment is available to halt disease progression. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene.

PTEN regulates AMPA receptor-mediated cell viability in iPS-derived motor neurons.

Excitatory transmission in the brain is commonly mediated by the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. In amyotrophic lateral sclerosis (ALS), AMPA receptors allow cytotoxic levels of calcium into neurons, contributing to motor neuron injury. We have previously shown that oculomotor neurons resistant to the disease process in ALS show reduced AMPA-mediated inward calcium currents compared with vulnerable spinal motor neurons.

The multifaceted role of glial cells in amyotrophic lateral sclerosis.

Despite indisputable progress in the molecular and genetic aspects of amyotrophic lateral sclerosis (ALS), a mechanistic comprehension of the neurodegenerative processes typical of this disorder is still missing and no effective cures to halt the progression of this pathology have yet been developed. Therefore, it seems that a substantial improvement of the outcome of ALS treatments may depend on a better understanding of the molecular mechanisms underlying neuronal pathology and survival as well as on the establishment of novel etiological therapeutic strategies. Noteworthy, a convergence of recent data from multiple studies suggests that, in cellular and animal models of ALS, a complex pathological interplay subsists between motor neurons and their non-neuronal neighbours, particularly glial cells.

Viral delivery of antioxidant genes as a therapeutic strategy in experimental models of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with no effective treatment to date. Despite its multi-factorial aetiology, oxidative stress is hypothesized to be one of the key pathogenic mechanisms. It is thus proposed that manipulation of the expression of antioxidant genes that are downregulated in the presence of mutant SOD1 may serve as a therapeutic strategy for motor neuronal protection.

Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS.

Fused in sarcoma (FUS) is a nuclear protein that carries a proline-tyrosine nuclear localization signal (PY-NLS) and is imported into the nucleus via Transportin (TRN). Defects in nuclear import of FUS have been implicated in neurodegeneration, since mutations in the PY-NLS of FUS cause amyotrophic lateral sclerosis (ALS). Moreover, FUS is deposited in the cytosol in a subset of frontotemporal lobar degeneration (FTLD) patients.

Transportin 1 accumulates specifically with FET proteins but no other transportin cargos in FTLD-FUS and is absent in FUS inclusions in ALS with FUS mutations.

Accumulation of the DNA/RNA binding protein fused in sarcoma (FUS) as inclusions in neurons and glia is the pathological hallmark of amyotrophic lateral sclerosis patients with mutations in FUS (ALS-FUS) as well as in several subtypes of frontotemporal lobar degeneration (FTLD-FUS), which are not associated with FUS mutations. Despite some overlap in the phenotype and neuropathology of FTLD-FUS and ALS-FUS, significant differences of potential pathomechanistic relevance were recently identified in the protein composition of inclusions in these conditions. While ALS-FUS showed only accumulation of FUS, inclusions in FTLD-FUS revealed co-accumulation of all members of the FET protein family, that include FUS, Ewing's sarcoma (EWS) and TATA-binding protein-associated factor 15 (TAF15) suggesting a more complex disturbance of transportin-mediated nuclear import of proteins in FTLD-FUS compared to ALS-FUS.

The BH4 domain of Bcl-X(L) rescues astrocyte degeneration in amyotrophic lateral sclerosis by modulating intracellular calcium signals.

Collective evidence indicates that motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is non-cell-autonomous and requires the interaction with the neighboring astrocytes. Recently, we reported that a subpopulation of spinal cord astrocytes degenerates in the microenvironment of motor neurons in the hSOD1(G93A) mouse model of ALS. Mechanistic studies in vitro identified a role for the excitatory amino acid glutamate in the gliodegenerative process via the activation of its inositol 1,4,5-triphosphate (IP(3))-generating metabotropic receptor 5 (mGluR5).

Phosphatase and tensin homologue/protein kinase B pathway linked to motor neuron survival in human superoxide dismutase 1-related amyotrophic lateral sclerosis.

Gene expression profiling has been used previously with spinal cord homogenates and laser capture microdissected motor neurons to determine the mechanisms involved in neurodegeneration in amyotrophic lateral sclerosis. However, while cellular and animal model work has focused on superoxide dismutase 1-related amyotrophic lateral sclerosis, the transcriptional profile of human mutant superoxide dismutase 1 motor neurons has remained undiscovered. The aim of this study was to apply gene expression profiling to laser captured motor neurons from human superoxide dismutase 1-related amyotrophic lateral sclerosis and neurologically normal control cases, in order to determine those pathways dysregulated in human superoxide dismutase 1-related neurodegeneration and to establish potential pathways suitable for therapeutic intervention.

Systemic delivery of scAAV9 expressing SMN prolongs survival in a model of spinal muscular atrophy.

Spinal muscular atrophy is one of the most common genetic causes of death in childhood, and there is currently no effective treatment. The disease is caused by mutations in the survival motor neuron gene. Gene therapy aimed at restoring the protein encoded by this gene is a rational therapeutic approach to ameliorate the disease phenotype.

PTEN depletion rescues axonal growth defect and improves survival in SMN-deficient motor neurons.

Phosphatase and tensin homolog (PTEN), a negative regulator of the mammalian target of rapamycin (mTOR) pathway, is widely involved in the regulation of protein synthesis. Here we show that the PTEN protein is enriched in cell bodies and axon terminals of purified motor neurons. We explored the role of the PTEN pathway by manipulating PTEN expression in healthy and diseased motor neurons.

Development and applications of non-HIV-based lentiviral vectors in neurological disorders.

Vectors based on non-HIV lentiviruses are opening up new approaches for the treatment of human disorders. These vectors efficiently deliver genes into many different types of cells from a broad range of species including man and the resulting gene expression is long-term. These features make them very attractive to be transformed into tools for gene therapy.

Deletion of the amino-terminal domain of the prion protein does not impair prion protein-dependent neuronal differentiation and neuritogenesis.

The cellular prion protein (PrP(C)) is a highly conserved glycoprotein of unknown biological function. To gain insight into the physiological role of PrP(C), we generated a novel PrP knockout cell line, named PrP(o/o) ML, by immortalization of neuroepithelial precursor cells derived from the cerebellum of PrP-knockout mice using the temperature-sensitive simian virus 40 (SV40) large T antigen. We demonstrated that the PrP(o/o) ML cell line is a unipotent precursor line with glutamatergic properties, which can acquire neuronal features when cultivated under specific conditions.

Focal degeneration of astrocytes in amyotrophic lateral sclerosis.

Astrocytes emerge as key players in motor neuron degeneration in Amyotrophic Lateral Sclerosis (ALS). Whether astrocytes cause direct damage by releasing toxic factors or contribute indirectly through the loss of physiological functions is unclear. Here we identify in the hSOD1(G93A) transgenic mouse model of ALS a degenerative process of the astrocytes, restricted to those directly surrounding spinal motor neurons.

Defective tumor necrosis factor-alpha-dependent control of astrocyte glutamate release in a transgenic mouse model of Alzheimer disease.

The cytokine tumor necrosis factor-alpha (TNFalpha) induces Ca2+-dependent glutamate release from astrocytes via the downstream action of prostaglandin (PG) E2. By this process, astrocytes may participate in intercellular communication and neuromodulation. Acute inflammation in vitro, induced by adding reactive microglia to astrocyte cultures, enhances TNFalpha production and amplifies glutamate release, switching the pathway into a neurodamaging cascade (Bezzi, P.

[Mechanism of action of quinapril in the treatment of primary arterial hypertension].

The effects of a long-term therapy with quinapril on plasma renin activity, plasma aldosterone, atrial natriuretic peptide and left ventricular mass were analysed in patients with mild to moderate systemic hypertension. Fifteen patients (4 women) were treated for one year with quinapril 10 or 20 mg once daily, reducing hereby the systolic and diastolic blood pressure from 167.5 +/- 11.

[24-hour ambulatory monitoring of arterial blood pressure and the sympathetic nervous system in hypertensive smokers].

Objective: To test the hypothesis that heavy smoking may interfere with the variation in ambulatory blood pressure (ABP) and sympathetic nervous system in essential hypertension.

Methods: We compared the office and 24-hour ABP of 48 untreated hypertensive smokers (> 20 cigarettes daily) with 90 non-smoking hypertensives matched for age, sex and body mass index. ABP was recorded using fully automatic SpaceLabs 90,207 units set to take a measurement every 15 minutes during the day (7.