Sclerosi Laterale Amiotrofica: SOD1 è implicata nel danno cellulare anche nei casi sporadici

Amyotrophic Lateral Sclerosis: SOD1 is also involved in sporadic cases’ cellular damage Amyotrophic Lateral Sclerosis (ALS) is a multifactorial pathology characterized by a progressive loss of motor neurons. In 20% of cases the presentation is familiar and it is related to specific and predisposing genetic factors. Mutations in sod1 gene have been identified in 2% of familiar cases which are likely to cause the mutated protein to gain toxic properties for cells. The analysis of post-mortem nervous tissues of sporadic ALS patients showed that oxidized SOD1 wild type (wt) protein has the same alterations as the mutated one. Sporadic ALS patients’ peripheral tissues, especially lymphocytes, have been demonstrated as reliable models of pathophysiological alterations of the disease and their use leads to remove the variability of data due to post mortem degradation of the tissues. Our study, through peripheral lymphocytes’ analysis, demonstrates the presence of misfolded and oxidized SOD1wt protein in sporadic ALS cases as well and examines its expression in cellular compartments. The correlation between biological data and clinical parameters shows how different SOD1 localizations could influence disease duration

Therapeutic strategies under development targeting inflammatory mechanisms in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurological disease characterized by the progressive loss of cortical, bulbar, and spinal motor neurons (MNs). The cardinal manifestation of ALS is a progressive paralysis which leads to death within a time span of 3 to 5 years after disease onset. Despite similar final output of neuronal death, the underlying pathogenic causes are various and no common cause of neuronal damage has been identified to date. Inflammation-mediated neuronal injury is increasingly recognized as a major factor that promotes disease progression and amplifies the MN death-inducing processes. The neuroimmune activation is not only a physiological reaction to cell-autonomous death but is an active component of nonautonomous cell death. Such injury-perpetuating phenomenon is now proved to be a common mechanism in many human disorders characterized by progressive neurodegeneration. Therefore, it represents an interesting therapeutic target. To date, no single cell population has been proved to play a major role. The existing evidence points to a complex cross talk between resident immune cells and nonresident cells, like monocytes and T lymphocytes, and to a dysregulation in cytokine profile and in phenotype commitment. After a summary of the most important mechanisms involved in the inflammatory reaction in ALS, this review will focus on novel therapeutic tools that rely on tackling inflammation to improve motor function and survival. Herein, completed, ongoing, or planned clinical trials, which aim to modify the rapidly fatal course of this disease, are discussed. Anti-inflammatory compounds that are currently undergoing preclinical study and novel suitable molecular targets are also mentioned

Applicazione della tecnica perfusione MRI nella valutazione del grado di malignità dei gliomi cerebrali

In the cerebral gliomas clinical practice, correct grading is really important. Establishing the correct lesion’s malignancy degree has relevant clinical implications, in terms of outcome and therapeutic strategies. Histopathologicalogical evaluation of cerebral gliomas sometime is difficult because of the impossibility of surgery or sampling mistakes, and imaging study with Magnetic Resonance provides morphological important information, but not so reliable for malignancy. During last years, there has been a considerable development of advanced RM techniques, which completes anatomy information, providing precious indications about the functionality of the investigated lesions. Perfusion represents the direct measure of the microvascularization of a tissue and can be used as a marker of imaging to estimate the tumor angiogenesis and the degree of malignancy. Our work aimed at evaluating the role of MR perfusion in establishing the correct grade of cerebral gliomas: we analysed perfusion maps of 22 patients affected by low grade or high grade gliomas, with or without histological confirmation, and after that we compared among tumor degrees II, III, IV and between simplified grade (low grade gliomas and high grade gliomas) with the main parameters of perfusion CBV (Cerbral Blood Volume) e CBF (Cerebral Blood Flow). A positive correlation has been found out between the two parameters and between the parameters and the cancer degree and this means that the bigger the degree of malignancy, the greater the perfusion is. This agrees with the histological datum that shows that the more consistent the vascularization, the more malignant the lesion is. It has been possible distinguishing between high grade gliomas and low grade gliomas throw the perfusion parameters, but it has not been possible to make a distinction between II/III and III/IV, because of the low number of patients suffering from grade III gliomas. Therefore, perfusion MR study might represent a useful instrument for the differential diagnosis between HGG and LGG, with relevant implications in the follow-up too. It’s still necessary to evaluate the discriminating power of the technique in the intermediate grade tumor

Mitochondrial Fusion Proteins and Human Diseases

Mitochondria are highly dynamic, complex organelles that continuously alter their shape, ranging between two opposite processes, fission and fusion, in response to several stimuli and the metabolic demands of the cell. Alterations in mitochondrial dynamics due to mutations in proteins involved in the fusion-fission machinery represent an important pathogenic mechanism of human diseases. The most relevant proteins involved in the mitochondrial fusion process are three GTPase dynamin-like proteins: mitofusin 1 (MFN1) and 2 (MFN2), located in the outer mitochondrial membrane, and optic atrophy protein 1 (OPA1), in the inner membrane. An expanding number of degenerative disorders are associated with mutations in the genes encoding MFN2 and OPA1, including Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy. While these disorders can still be considered rare, defective mitochondrial dynamics seem to play a significant role in the molecular and cellular pathogenesis of more common neurodegenerative diseases, for example, Alzheimer’s and Parkinson’s diseases. This review provides an overview of the basic molecular mechanisms involved in mitochondrial fusion and focuses on the alteration in mitochondrial DNA amount resulting from impairment of mitochondrial dynamics. We also review the literature describing the main disorders associated with the disruption of mitochondrial fusion

Effect of Combined Systemic and Local Morpholino Treatment on the Spinal Muscular Atrophy Δ7 Mouse Model Phenotype

BACKGROUND: Spinal muscular atrophy (SMA) is a fatal motor neuron disease of childhood that is caused by mutations in the SMN1 gene. Currently, no effective treatment is available. One possible therapeutic approach is the use of antisense oligos (ASOs) to redirect the splicing of the paralogous gene SMN2, thus increasing functional SMN protein production. Various ASOs with different chemical properties are suitable for these applications, including a morpholino oligomer (MO) variant with a particularly excellent safety and efficacy profile. OBJECTIVE: We investigated a 25-nt MO sequence targeting the negative intronic splicing silencer (ISS-N1) 10 to 34 region. METHODS: We administered a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) in the SMAΔ7 mouse model and evaluated the effect and neuropathologic phenotype. We tested different concentrations (from 2 to 24 nM) and delivery protocols (intracerebroventricular injection, systemic injection, or both). We evaluated the treatment efficacy regarding SMN levels, survival, neuromuscular phenotype, and neuropathologic features. RESULTS: We found that a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) exhibited superior efficacy in transgenic SMAΔ7 mice compared with previously described sequences. In our experiments, the combination of local and systemic administration of MO (bare or conjugated to octaguanidine) was the most effective approach for increasing full-length SMN expression, leading to robust improvement in neuropathologic features and survival. Moreover, we found that several small nuclear RNAs were deregulated in SMA mice and that their levels were restored by MO treatment. CONCLUSION: These results indicate that MO-mediated SMA therapy is efficacious and can result in phenotypic rescue, providing important insights for further development of ASO-based therapeutic strategies in SMA patients

Histological effects of givinostat in boys with Duchenne muscular dystrophy

Duchenne Muscular Dystrophy (DMD) is caused by mutations in the dystrophin gene leading to dystrophin deficiency, muscle fiber degeneration and progressive fibrotic replacement of muscles. Givinostat, a histone deacetylase (HDAC) inhibitor, significantly reduced fibrosis and promoted compensatory muscle regeneration in mdx mice. This study was conducted to evaluate whether the beneficial histological effects of Givinostat could be extended to DMD boys. Twenty ambulant DMD boys aged 7 to <11 years on stable corticosteroid treatment were enrolled in the study and treated for ≥12 months with Givinostat. A muscle biopsy was collected at the beginning and at the end of treatment to evaluate the amount of muscle and fibrotic tissue. Histological effects were the primary objectives of the study. Treatment with Givinostat significantly increased the fraction of muscle tissue in the biopsies and reduced the amount of fibrotic tissue. It also substantially reduced tissue necrosis and fatty replacement. Overall the drug was safe and tolerated. Improvement in functional tests was not observed in this study, but the sample size of the study was not sufficient to draw definitive conclusions. This study showed that treatment with Givinostat for more than 1 year significantly counteracted histological disease progression in ambulant DMD boys aged 7 to 10 years