Federico Casale

NADPH oxidase 2 (NOX2) enzyme activation in patients with chronic inflammatory demyelinating polyneuropathy

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immunomediated condition affecting the peripheral nervous system where probably macrophages are the primary effector cells for demyelination. Reactive oxygen species (ROS), catalyzed by the NOX family of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzymes, can induce peroxidation and are potentially injurious to myelin. Our aim was to assess the activity of NOX2, an isoform of NOX, in a series of CIDP patients and to analyze the effect of intravenous immunoglobulin (IVIg) on NOX2.

Amyotrophic lateral sclerosis and food intake

Abstract Objective: To verify if specific foods and nutrients could be risk factors or protective factors for amyotrophic lateral sclerosis (ALS). Methods: Patients with newly diagnosed ALS from three Italian administrative regions were included. For each patient, a healthy control, matched for age (±5 years), sex and administrative region of residence, was selected by a general practitioner. Cases and controls were interviewed by a trained investigator who filled a validated and reproducible food-frequency questionnaire. Daily intake of macronutrients, micronutrients, fatty acids, and total energy were estimated using an Italian food composition database. Results: Two hundred and twelve cases and 212 controls were included. A risk reduction was found for coffee and tea (odds ratios (OR) = 0.29, 95% CI 0.14–0.60), whole bread (OR = 0.55, 95% CI 0.31–0.99), raw vegetables (OR = 0.25, 95% CI 0.13–0.52) and citrus fruits (OR = 0.49, 95% CI 0.25–0.97). A risk increase was observed for red meat (OR = 2.96, 95% CI 1.46–5.99) and pork and processed meat (OR = 3.87, 95% CI 1.86–8.07). An increased risk was found for total protein (OR = 2.96, 95% CI 1.08–8.10), animal protein (OR = 2.91, 95% CI 1.33–6.38), sodium (OR = 3.96, 95% CI 1.45–10.84), zinc (OR = 2.78, 95% CI 1.01–7.83) and glutamic acid (OR = 3.63, 95% CI 1.08–12.2). Conclusions: Some foods/nutrients may be risk factors and others protective factors for ALS.

Common polymorphisms of chemokine (C-X3-C motif) receptor 1 gene modify amyotrophic lateral sclerosis outcome: A population-based study: CX3CR1 Gene and ALS Outcome

Introduction: In the brain, the chemokine (C‐X3‐C motif) receptor 1 (1CX3CR1) gene is expressed only by microglia, where it acts as a key mediator of the neuron–microglia interactions. We assessed whether the 2 common polymorphisms of the CX3CR1 gene (V249I and T280M) modify amyotrophic lateral sclerosis (ALS) phenotype. Methods: The study included 755 ALS patients diagnosed in Piemonte between 2007 and 2012 and 369 age‐matched and sex‐matched controls, all genotyped with the same chips. Results: Neither of the variants was associated with an increased risk of ALS. Patients with the V249I V/V genotype had a 6‐month‐shorter survival than those with I/I or V/I genotypes (dominant model, P = 0.018). The T280M genotype showed a significant difference among the 3 genotypes (additive model, P = 0.036). Cox multivariable analysis confirmed these findings. Discussion: We found that common variants of the CX3CR1 gene influence ALS survival. Our data provide further evidence for the role of neuroinflammation in ALS. Muscle Nerve 57: 212–216, 2018

Common polymorphisms of chemokine (C‐X3‐C motif) receptor 1 gene modify amyotrophic lateral sclerosis outcome: A population‐based study

Introduction: In the brain, the chemokine (C‐X3‐C motif) receptor 1 (1CX3CR1) gene is expressed only by microglia, where it acts as a key mediator of the neuron–microglia interactions. We assessed whether the 2 common polymorphisms of the CX3CR1 gene (V249I and T280M) modify amyotrophic lateral sclerosis (ALS) phenotype. Methods: The study included 755 ALS patients diagnosed in Piemonte between 2007 and 2012 and 369 age‐matched and sex‐matched controls, all genotyped with the same chips. Results: Neither of the variants was associated with an increased risk of ALS. Patients with the V249I V/V genotype had a 6‐month‐shorter survival than those with I/I or V/I genotypes (dominant model, P = 0.018). The T280M genotype showed a significant difference among the 3 genotypes (additive model, P = 0.036). Cox multivariable analysis confirmed these findings. Discussion: We found that common variants of the CX3CR1 gene influence ALS survival. Our data provide further evidence for the role of neuroinflammation in ALS. Muscle Nerve 57: 212–216, 2018

NADPH oxidases 2 activation in patients with Parkinson's disease

Fig. 1. Mean fluorescence intensity (MFI) of oxidative burst in granulocytes (up) and monocytes (down) of PD patients and related controls after stimulation with bacterial stimulus (E. Coli). Neutrophils provide the first line of defense of the innate immune system by phagocytosing, killing, and digesting bacteria. Killing was previously believed to be accomplished by oxygen free radicals and other reactive oxygen species (ROS) generated by the NADPH oxidase in a process called “respiratory burst”. NADPH oxidase (NOX) enzymes catalyze the formation of ROS, which play a role in the development of different neurological disorders (ND), particularly whose generated by the phagocytic isoform NOX2 that is highly expressed in activated phagocytes including neutrophils and microglia [1], where it is responsible for the respiratory oxidative burst. Increased ROS has been observed in Amyotrophic Lateral Sclerosis (ALS), and a lower NOX2 activity showed a significant increase of survival in ALS patients [2]. There is also evidence that NOX are expressed and activated in patients with Parkinsons Disease (PD) and other ND, though the underlying mechanisms of NOX2mediated oxidative stress in PD pathogenesis are still unknown [3]. To elucidate the links between NOX2 and PD, the aim of this study was to evaluate the enzyme activity measuring oxidative burst of granulocytes and monocytes (ROS production) in fresh whole blood of patients in comparison with matched healthy controls using PhagoburstTM assay by flow cytometry, according to the manufacturers instructions. A total of 40 consecutive patients, 20 men and 20 women (64.7± 8.4 mean age and SD) with diagnosis of idiopathic PD and 40 healthy sexand age-matched control subjects (65.1± 8.6) were enrolled in the study. Patients were recruited at the Parkinsons andMovement Disorders Clinic, ‘Rita Levi Montalcini’ Department of Neurosciences, University of Turin, Italy. 18 subjects were inpatients, 22 outpatients. The study was approved by local Ethic Committee; both patients and controls provided the signed informed consent and personal data were treated according to the current Italian directives (Law No. 196 of 30 June 2003). Diagnosis of PD was made according to the UK Brain Bank criteria by a neurologist expert in movement disorder. The disease duration was 14.4 ± 6.3 years; 95% of patients (38/ 40) were in levodopa þ benserazide treatment. UPDRS of inpatients was 24± 8 (average of the differences of UPDRS OFF score versus UPDRS ON score calculated for each

A novel p.Ser108LeufsTer15 SOD1 mutation leading to the formation of a premature stop codon in an apparently sporadic ALS patient: insights into the underlying pathomechanisms

We report an apparently sporadic amyotrophic lateral sclerosis patient carrying a heterozygous novel frameshift SOD1 mutation (p.Ser108LeufsTer15), predicted to cause a premature protein truncation. RT-PCR analysis of SOD1 mRNA and SDS-PAGE/Western blot analysis of PBMC demonstrated that mRNA from the mutant allele is expressed at levels similar to those of the wild-type allele, but the truncated protein is undetectable also in the insoluble fraction and after proteasome inhibition. Accordingly, the dismutation activity in erythrocytes is halved. Thus, the pathogenic mechanism associated with this mutation might be based on an insufficient activity of SOD1 that would make motor neurons more vulnerable to oxidative injury. However, it cannot be excluded that p.Ser108LeufsTer15 SOD1 is present in the nervous tissue and, being less charged and hence having less repulsive forces than the wild-type protein, may trigger toxic mechanisms as a consequence of its propensity to aggregate.

Common polymorphisms of CX3CR1 gene modify ALS outcome: A population-based study.

Introduction: In the brain, the chemokine (C‐X3‐C motif) receptor 1 (1CX3CR1) gene is expressed only by microglia, where it acts as a key mediator of the neuron–microglia interactions. We assessed whether the 2 common polymorphisms of the CX3CR1 gene (V249I and T280M) modify amyotrophic lateral sclerosis (ALS) phenotype. Methods: The study included 755 ALS patients diagnosed in Piemonte between 2007 and 2012 and 369 age‐matched and sex‐matched controls, all genotyped with the same chips. Results: Neither of the variants was associated with an increased risk of ALS. Patients with the V249I V/V genotype had a 6‐month‐shorter survival than those with I/I or V/I genotypes (dominant model, P = 0.018). The T280M genotype showed a significant difference among the 3 genotypes (additive model, P = 0.036). Cox multivariable analysis confirmed these findings. Discussion: We found that common variants of the CX3CR1 gene influence ALS survival. Our data provide further evidence for the role of neuroinflammation in ALS. Muscle Nerve 57: 212–216, 2018