An Inducer of VGF Protects Cells against ER Stress-Induced Cell Death and Prolongs Survival in the Mutant SOD1 Animal Models of Familial ALS

Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease, and recent evidence has suggested that endoplasmic reticulum (ER) stress signaling is involved in the pathogenesis of ALS. Here we identified a small molecule, SUN N8075, which has a marked protective effect on ER stress-induced cell death, in an in vitro cell-based screening, and its protective mechanism was mediated by an induction of VGF nerve growth factor inducible (VGF): VGF knockdown with siRNA completely abolished the protective effect of SUN N8075 against ER-induced cell death, and overexpression of VGF inhibited ER-stress-induced cell death. VGF level was lower in the spinal cords of sporadic ALS patients than in the control patients. Furthermore, SUN N8075 slowed disease progression and prolonged survival in mutant SOD1 transgenic mouse and rat models of ALS, preventing the decrease of VGF expression in the spinal cords of ALS mice. These data suggest that VGF plays a critical role in motor neuron survival and may be a potential new therapeutic target for ALS, and SUN N8075 may become a potential therapeutic candidate for treatment of ALS

Longitudinal Tracking of Human Fetal Cells Labeled with Super Paramagnetic Iron Oxide Nanoparticles in the Brain of Mice with Motor Neuron Disease

Stem Cell (SC) therapy is one of the most promising approaches for the treatment of Amyotrophic Lateral Sclerosis (ALS). Here we employed Super Paramagnetic Iron Oxide nanoparticles (SPIOn) and Hoechst 33258 to track human Amniotic Fluid Cells (hAFCs) after transplantation in the lateral ventricles of wobbler (a murine model of ALS) and healthy mice. By in vitro, in vivo and ex vivo approaches we found that: 1) the main physical parameters of SPIOn were maintained over time; 2) hAFCs efficiently internalized SPIOn into the cytoplasm while Hoechst 33258 labeled nuclei; 3) SPIOn internalization did not alter survival, cell cycle, proliferation, metabolism and phenotype of hAFCs; 4) after transplantation hAFCs rapidly spread to the whole ventricular system, but did not migrate into the brain parenchyma; 5) hAFCs survived for a long time in the ventricles of both wobbler and healthy mice; 6) the transplantation of double-labeled hAFCs did not influence mice survival

Supportive and symptomatic management of amyotrophic lateral sclerosis

The main aims in the care of individuals with amyotrophic lateral sclerosis (ALS) are to minimize morbidity and maximize quality of life. Although no cure exists for ALS, supportive and symptomatic care provided by a specialist multidisciplinary team can improve survival. The basis for supportive management is shifting from expert consensus guidelines towards an evidence-based approach, which encourages the use of effective treatments and could reduce the risk of harm caused by ineffective or unsafe interventions. For example, respiratory support using noninvasive ventilation has been demonstrated to improve survival and quality of life, whereas evidence supporting other respiratory interventions is insufficient. Increasing evidence implicates a causal role for metabolic dysfunction in ALS, suggesting that optimizing nutrition could improve quality of life and survival. The high incidence of cognitive dysfunction and its impact on prognosis is increasingly recognized, although evidence for effective treatments is lacking. A variety of strategies are used to manage the other physical and psychological symptoms, the majority of which have yet to be thoroughly evaluated. The need for specialist palliative care throughout the disease is increasingly recognized. This Review describes the current approaches to symptomatic and supportive care in ALS and outlines the current guidance and evidence for these strategies

Neuroimaging in primary lateral sclerosis

Increased interest in the underlying pathogenesis of primary lateral sclerosis (PLS) and its relationship to amyotrophic lateral sclerosis (ALS) has corresponded to a growing number of CNS imaging studies, especially in the past decade. Both its rarity and uncertainty of definite diagnosis prior to 4 years from symptom onset have resulted in PLS being less studied than ALS. In this review, we highlight most relevant papers applying magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET) to analyzing CNS changes in PLS, often in relation to ALS. In patients with PLS, mostly brain, but also spinal cord has been evaluated since significant neurodegeneration is essentially restricted to upper motor neuron (UMN) structures and related pathways. Abnormalities of cortex and subcortical white matter tracts have been identified by structural and functional MRI and MRS studies, while metabolic and cell-specific changes in PLS brain have been revealed using various PET radiotracers. Future neuroimaging studies will continue to explore the interface between the PLS-ALS continuum, identify more changes unique to PLS, apply novel MRI and MRS sequences showing greater structural and neurochemical detail, as well as expand the repertoire of PET radiotracers that reveal various cellular pathologies. Neuroimaging has the potential to play an important role in the evaluation of novel therapies for patients with PLS

The size distribution of neurons in the motor cortex in amyotrophic lateral sclerosis

The motor cortex of eight patients with amyotrophic lateral sclerosis (ALS) and nine control subjects was used in the study. Recent stereological tools, the disector and the rotator method, were applied to the motor cortex of patients with ALS and control subjects to obtain estimates of mean perikaryon volume, mean neuronal nuclear volume, total perikaryon volume and total neuronal nuclear volume. No significant differences were found in any of the estimates. In vivo proton magnetic resonance spectroscopy studies show a decrease in the concentration of neuronal markers. We expected to find changes in perikaryon and/or nuclei neuronal volume because the total neuron number is unchanged in ALS compared with control subjects. However, this was not the case; our results suggest that metabolic changes take place in the motor cortex of ALS patients without these concomitant anatomical changes