Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease

Amyloid-β proteins (Aβ) of 42 (Aβ42) and 40 aa (Aβ40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer's disease (AD). A number of rare mutations linked to familial AD (FAD) on the Aβ precursor protein (APP), Presenilin-1 (PS1), Presenilin- 2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the ε4 allele of Apolipoprotein E (ApoE-ε4) foster the accumulation of Aβ and also induce the entire spectrum of pathology associated with the disease. Aβ accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by β-site APP cleaving enzyme (BACE1) and γ-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate Aβ. Although Aβ accumulates in all forms of AD, the only pathways known to be affected in FAD increase Aβ production by APP gene duplication or via base substitutions on APP and γ-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer Aβ42 or both Aβ40 and Aβ42. However, the vast majority of AD patients accumulate Aβ without these known mutations. This led to proposals that impairment of Aβ degradation or clearance may play a key role in AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of γ-secretase inhibitors to paradoxically increase the yield of Aβ and we have recently established that the mechanism is by skirting Aβ degradation. This review outlines major cellular pathways of Aβ degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for Aβ turnover

Health-related quality of life and functional changes in DMD:A 12-month longitudinal cohort study

Family caregivers of people with amyotrophic lateral sclerosis (ALS) live stressful lives in which they spend most of their time caring for their loved ones and managing difficult situations, thereby reducing the time spent in taking care of themselves. This situation may last several years. Previous literature has widely highlighted that this situation reduces caregivers' quality of life and increases their psychological distress and risk of health problems, but there is a lack of studies that focus on psychological interventions for these situations. This qualitative study examined a pilot experience of two mutual support groups for family caregivers of people with ALS. The aim was to identify caregivers' needs, the prominent aspects of their experience, and to understand whether and how this intervention strategy might help them. Six partners (four men and two women) and six adult children (five women and one man) participated in the groups, which were conducted in northern Italy. After the support groups finished, participants underwent semi-structured interviews. The authors conducted a content analysis of the transcripts of the interviews and the 20 group sessions. The thematic areas identified were "caregiving," "being the son/daughter of a person with ALS," "being the partner of a person with ALS," "group experience" and "group evaluation." The caregiving experience was profoundly different depending on whether the caregiver was a son/daughter or a partner of a patient with ALS. Moreover, comparison with peers and mutual support helped participants to better cope with ALS and its consequences, to improve their care for their relatives and to overcome typical caregiver isolation. These results suggest the usefulness of involving communities in caregiver support in order to create new networks and activate personal and social resources for well-being

Revised North Star Ambulatory Assessment for Young Boys with Duchenne Muscular Dystrophy

The advent of therapeutic approaches for Duchenne muscular dystrophy (DMD) has highlighted the need to identify reliable outcome measures for young boys with DMD. The aim of this study was to develop a revised version of the North Star Ambulatory Assessment (NSAA) suitable for boys between the age of 3 and 5 years by identifying age appropriate items and revising the scoring system accordingly. Using the scale in 171 controls between the age of 2.9 and 4.8 years, we identified items that were appropriate at different age points. An item was defined as age appropriate if it was completed, achieving a full score, by at least 85% of the typically developing boys at that age. At 3 years (±3months) there were only 8 items that were age appropriate, at 3 years and 6 months there were 13 items while by the age of 4 years all 17 items were appropriate. A revised version of the scale was developed with items ordered according to the age when they could be reliably performed. The application of the revised version of the scale to data collected in young DMD boys showed that very few of the DMD boys were able to complete with a full score all the age appropriate items. In conclusion, our study suggests that a revised version of the NSAA can be used in boys from the age of 3 years to obtain information on how young DMD boys acquire new abilities and how this correlates with their peers

Inhibition of Hypoxia-Inducible Factor-1α (HIF-1α) Protein Synthesis by DNA damage inducing agents

10.1371/journal.pone.0010522PLoS ONE55

Why orthotic devices could be of help in the management of Movement Disorders in the young

BACKGROUND: Movement Disorders (MD) are a class of disease that impair the daily activities of patients, conditioning their sensorimotor, cognitive and behavioural capabilities. Nowadays, the general management of patients with MD is based on rehabilitation, pharmacological treatments, surgery, and traditional splints. Although some attempts have been made to devise specific orthoses for the rehabilitation of patients affected by MD, especially the younger ones, those devices have received limited attention. MAIN BODY: This paper will principally discuss the case of upper limb rehabilitation in Childhood Dyskinesia (CD), a complex motor disease that affects paediatric patients. Through a critical review of the present solutions and a discussion about the neurophysiological characteristics of the disease, the study will lead to the formulation of desirable features of a possible new upper-limb orthosis. CONCLUSIONS: Design principles will be derived to provide specialised orthoses for the dynamic control of posture and the stabilisation of voluntary movements: those include using biomechanical actions and enhanced proprioception to support the sensorimotor rehabilitation of the children affected by CD. A similar approach could be advantageously applied in other MD-related conditions, especially with hyperkinetic and/or hypertonic traits

Protein/DNA interactions in complex DNA topologies: expect the unexpected

DNA supercoiling results in compacted DNA structures that can bring distal sites into close proximity. It also changes the local structure of the DNA, which can in turn influence the way it is recognised by drugs, other nucleic acids and proteins. Here, we discuss how DNA supercoiling and the formation of complex DNA topologies can affect the thermodynamics of DNA recognition. We then speculate on the implications for transcriptional control and the three-dimensional organisation of the genetic material, using examples from our own simulations and from the literature. We introduce and discuss the concept of coupling between the multiple length-scales associated with hierarchical nuclear structural organisation through DNA supercoiling and topology

Structural diversity of supercoiled DNA

By regulating access to the genetic code, DNA supercoiling strongly affects DNA metabolism. Despite its importance, however, much about supercoiled DNA (positively supercoiled DNA, in particular) remains unknown. Here we use electron cryo-tomography together with biochemical analyses to investigate structures of individual purified DNA min icircle topoisomers with defined degrees of supercoiling. Our results reveal that each topoisomer, negative or positive, adopts a unique and surprisingly wide distribution of three-dimensional conformations. Moreover, we uncover striking differences in how the topoisomers handle torsional stress. As negative supercoiling increases, bases are increasingly exposed. Beyond a sharp supercoiling threshold, we also detect exposed bases in positively supercoiled DNA. Molecular dynamics simulations independently confirm the conformational heterogeneity and provide atomistic insight into the flexibility of supercoiled DNA. Our integrated approach reveals the three-dimensional structures of DNA that are essential for its function

Longitudinal changes in respiratory and upper limb function in a pediatric type III spinal muscular atrophy cohort after loss of ambulation

Introduction/Aims: Spinal muscular atrophy (SMA) type III is a relatively mild form of SMA. Few studies have investigated the changes in both respiratory and upper limb function within this population after loss of ambulation. The aim of this study was to assess change in percentage of predicted forced vital capacity (FVC% predicted) and change in the Revised Upper Limb Module (RULM) score in these patients throughout a 24-month period after loss of ambulation. Effect of scoliosis and its surgical correction, disease duration since loss of ambulation, weight, and height were also investigated. / Methods: Retrospective analyses were performed on 24 nonambulant SMA III patients from data collected at two centers in the United Kingdom. / Results: The FVC% predicted score showed a significant progressive deterioration of 17% over the 24-month period. Respiratory deterioration correlated significantly with age, weight, disease duration since loss of ambulation, and spinal correctional surgery. Longitudinal RULM data were available for 16 patients; a significant deterioration was observed with a mean decrease in score of 3 over 24 months. Age correlated negatively with RULM score, as did height and time since loss of ambulation. A significant positive correlation between FVC% predicted and RULM was demonstrated. / Discussion: This study highlights how SMA type III patients have progressive deterioration of respiratory and upper limb function after loss of ambulation. Combining data from these assessments could provide insight into clinical progression, inform clinical trials, and provide assistance in managing disease progression expectations for patients

Type I spinal muscular atrophy and disease modifying treatments: a nationwide study in children born since 2016

Background The advent of disease-modifying treatments (DMT) has changed natural history in 5q Spinal muscular atrophy (SMA). The aim of this study was to report survival and functional aspects in all the Italian type I children born since 2016. Methods The study included all symptomatic children with type I SMA born since January 1st, 2016, when DMTs became available in Italy. All the Italian SMA referral centers provided data on survival and motor, respiratory, and nutritional status. To compare survival rate pre and post DMTs approval, we also included similar data from SMA patients born between January 1st, 2010, and December 31st, 2015. A two-proportion z-test was conducted compare the two cohorts. The significance level was set at p < .05. Findings 241 infants (98%) had type I SMA. Mean follow-up was 3.48 years (SD 2.33). Among type I patients, 42/241 did not survive (25 untreated), while 199 were alive at last follow-up (all treated; mean treatment age 0.6 years), with 25 needing >16 h/day ventilation or tracheostomy with continuous invasive ventilation. 130 of the 199 survivors (65%) achieved independent sitting, and 175 (87.9%) did not require tube feeding. Interpretation Our study provides a picture of the ' new natural history' of type I SMA, confirming the impact of the new therapies on the progression of type I with longer survival r and has better motor, respiratory and nutritional. Funding This research was partially funded by grants from the Italian Ministry of Health