Mitochondrial dysfunctions in neurodegenerative diseases:role in disease pathogenesis,strategies for analysis and therapeutic prospects

Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes,the mitochondria are required for multiple pivotal processes that include the production of biological energy,the biosynthesis of reactive oxygen species,the control of calcium homeostasis,and the triggering of cell death.The disruption of anyone of these processes has been shown to impact strongly the function of all cells,but especially of neurons.In this review,we discuss the role of the mitochondria impairment in the development of the neurodegenerative diseases Amyotrophic Lateral Sclerosis,Parkinson's disease and Alzheimer's disease.We highlight how mitochondria disruption revolves around the processes that underlie the mitochondria's life cycle:fusion,fission,production of reactive oxygen species and energy failure.Both genetic and sporadic forms of neurodegenerative diseases are unavoidably accompanied with and often caused by the dysfunction in one or more of the key mitochondrial processes.Therefore,in order to get in depth insights into their health status in neurodegenerative diseases,we need to focus into innovative strategies aimed at characterizing the various mitochondrial processes.Current techniques include Mitostress,Mitotracker,transmission electron microscopy,oxidative stress assays along with expression measurement of the proteins that maintain the mitochondrial health.We will also discuss a panel of approaches aimed at mitigating the mitochondrial dysfunction.These include canonical drugs,natural compounds,supplements,lifestyle interventions and innovative approaches as mitochondria transplantation and gene therapy.In conclusion,because mitochondria are fundamental organelles necessary for virtually all the cell functions and are severely impaired in neurodegenerative diseases,it is critical to develop novel methods to measure the mitochondrial state,and novel therapeutic strategies aimed at improving their health.

Type 1 diabetes and celiac disease:The effects of gluten free diet on metabolic control

Type 1 diabetes mellitus is associated with celiac disease,with a prevalence that varies between 0.6% and 16.4%,according to different studies.After a diagnosis of celiac disease is confirmed by small bowel biopsy,patients are advised to commence a gluten-free diet(GFD).This dietary restriction may be particularly difficult for the child with diabetes,but in Europe(and in Italy) many food stores have targeted this section of the market with better labeling of products and more availability of specific GFD products.Treatment with a GFD in symptomatic patients has been shown to improve the symptoms,signs and complications of celiac disease.However,the effects of a GFD on diabetic control are less well established.Initial reports of improved hypoglycemic control were based on children who were diagnosed with celiac disease associated with malabsorption,but there have subsequently been reports of improvement in patients with type 1 diabetes with subclinical celiac disease.There are other studies reporting no effect,improved control and an improvement of hypoglycemic episodes.Moreover,in this review we wish to focus on low glycemic index foods,often suggested in people with type 1 diabetes,since they might reduce postprandial glycemic excursion and enhance longterm glycemic control.In contrast,GFD may be rich in high glycemic index foods that can increase the risk of obesity,insulin resistance and cardiovascular disease,worsening the metabolic control of the child with diabetes.Hence,it is important to evaluate the impact of a GFD on metabolic control,growth and nutritional status in children with type 1 diabetes.

Explaining the increased mortality in type 1 diabetes

Despite large improvements in the management of glucose levels and in the treatment of cardiovascular risk factors,the mortality rate in individuals with type 1 diabetes(T1D) is still high.Recently,Lind et al found that T1 D individuals with glycated hemoglobin levels of 6.9% or lower had a risk of death from any cause or from cardiovascular causes that is twice as high as the risk for matched controls.T1 D is a chronic disease with an early onset(e.g.,pediatric age) and thus in order to establish a clear correlation between death rate and the glycometabolic control,the whole history of glycemic control should be considered; particularly in the early years of diabetes.The switch from a normoto hyperglycemic milieu in an individual with T1 D in the pediatric age,represents a stressful event that may impact outcomes and death rate many years later.In this paper we will discuss the aforementioned issues,and offer our view on these findings,paying a particular attention to the several alterations occurring in the earliest phases of T1 D and to the many factors that may be associated with the chronic history of T1 D.This may help us to better understand the recently published death rate data and to develop future innovative and effective preventive strategies.

Proteinuria in paediatric patients with human immunodefi ciency virus infection

In human immunodef iciency virus(HIV)-infected people kidney disease is as an important cause of morbidity and mortality. Clinical features of kidney damage in HIV-infected patients range from asymptomatic microalbuminuria to nephrotic syndrome. The lack of specif ic clinical features despite the presence of heavy proteinuria may mask the renal involvement. Indeed, it is important in HIV patients to monitor renal function to early discover a possible kidney injury. After the introduction of antiretroviral therapy, mortality and morbidity associated to HIV-infection have shown a substantial reduction, although a variety of side effects for longterm use of highly active antiretroviral therapy, including renal toxicity, has emerged. Among more than 20 currently available antiretroviral agents, many of them can occasionally cause reversible or irreversible nephrotoxicity. At now, three antiretroviral agents, i.e., indinavir, atazanavir and tenofovir disoproxil fumarate have a well established association with direct nephrotoxicity. This review focuses on major causes of proteinuria and other pathological f indings related to kidney disease in HIV-infected children and adolescents.

Impact of new technologies on diabetes care

Technologies for diabetes management,such as continuous subcutaneous insulin infusion(CSII)and continuous glucose monitoring(CGM)systems,have improved remarkably over the last decades.These developments are impacting the capacity to achieve recommended hemoglobin A1c levels and assisting in preventing the development and progression of microand macro vascular complications.While improvements in metabolic control and decreases in risk of severe and moderate hypoglycemia have been described with use of these technologies,large epidemiological international studies show that many patients are still unable to meet their glycemic goals,even when these technologies are used.This editorial will review the impact of technology on glycemic control,hypoglycemia and quality of life in children and youth with type 1 diabetes.Technologies reviewed include CSII,CGM systems and sensoraugmented insulin pumps.In addition,the usefulness of advanced functions such as bolus profiles,bolus calculators and threshold-suspend features will be also discussed.Moreover,the current editorial will explore the challenges of using these technologies.Indeed,despite the evidence currently available of the potential benefits of using advanced technologies in diabetes management,many patients still report barriers to using them.Finally this article will highlight the importance of future studies tailored toward overcome these barriers to optimizing glycemic control and avoiding severe hypoglycemia.

Cerebral ultrasound abnormalities in offsprings of women with C677T homozygous mutation in the MTHFR gene:a prospective study

Background:Perinatal stroke is a common cause of neurologic disability.Being clinically under-recognized,its true incidence is not known.Maternal thrombophilia is likely to be a predisposing factor.To date,a general consensus for evaluation of babies born to mothers with genetic thrombotic predisposition is missing.This study was undertaken to assess the frequency of cerebral abnormalities in the offspring of women with homozygous C677T mutation in the MTHFR gene,and to seek for association with additional maternal or pregnancy risk factors.Methods:Mother-infant pairs were consecutively recruited from October 2006 through February 2013.Neonates underwent a thorough physical examination at birth,and a cerebral ultrasound examination(cUS)was performed within 24 hours of their life.In neonates with major cerebral lesions,a thrombophilia panel test was obtained.Follow-up cUS was performed in babies with major or minor cerebral abnormalities.Results:Ninety-one neonates(47 males)were enrolled.By cUS,abnormalities were detected in 18(19.8%)neonates.Twelve neonates were diagnosed with a minor lesion;a major ischemic/hemorrhagic lesion was found in 6 neonates.There were a neat male preponderance and significant associations with a history of suspected miscarriage,maternal coagulation factors gene mutations,and reduced protein S or protein C activity.Conclusions:Our data confirmed a high incidence of cerebral abnormalities in neonates born to women with C677T homozygous mutation in the MTHFR gene.cUS at birth proved to be an effective screening tool or a diagnostic test,that should be routinely performed in babies born to mothers with known thrombotic predisposition.

Hydroxychloroquine modulates immunological pathways activated by RNA:DNA hybrids in Aicardi–Goutières syndrome patients carrying RNASEH2 mutations

Aicardi–Goutières syndrome(AGS)is a rare genetic disease caused by mutations in nine genes that are all involved in nucleic acid metabolism or sensing.1,2 The three RNASEH2 subunits represent the most frequently mutated genes in AGS patients,1,3 and mutations in RNASEH2 subunits lead to the accumulation of endogenous RNA:DNA hybrids that may trigger an interferon-α-mediated immune response4 through the activation of pattern recognition receptors(PRRs).5 PRRs perform surveillance on extracellular,endosomal,and cytosolic compartments to identify signs of infection:endogenous nucleic acids that are inappropriately cleared may enter and accumulate in the cytoplasm,driving inflammation and autoimmune diseases.6 This accumulation may be the cause of the clinical autoimmune phenotype of AGS patients carrying RNASEH2 mutations.A proven effective cure for AGS has not been discovered,and targeting these two pathways may lead to a treatment that improves patients’immunological symptoms.Hydroxychloroquine(HCQ)interferes with normal antigen processing and presentation and is widely used in the clinical treatment of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis.7 HCQ is also a well-known inhibitor of autophagy that prevents the degradation of autolysosomes.This drug inhibits acidification and maturation of endosomes and increases the pH in lysosomes,resulting in the inhibition of their main functions,such as downstream cell signaling through TLRs.7 Therefore,the aim of our work was to investigate whether HCQ is able to modulate the abnormal inflammatory response driven by RNA:DNA hybrids.