Human stem cell models of neurodegeneration: a novel approach to study mechanisms of disease development

The number of patients with neurodegenerative diseases is increasing significantly worldwide. Thus, intense research is being pursued to uncover mechanisms of disease development in an effort to identify molecular targets for therapeutic intervention. Analysis of postmortem tissue from patients has yielded important histological and biochemical markers of disease progression. However, this approach is inherently limited because it is not possible to study patient neurons prior to degeneration. As such, transgenic and knockout models of neurodegenerative diseases are commonly employed. While these animal models have yielded important insights into some molecular mechanisms of disease development, they do not provide the opportunity to study mechanisms of neurodegeneration in human neurons at risk and thus, it is often difficult or even impossible to replicate human pathogenesis with this approach. The generation of patient-specific induced pluripotent stem (iPS) cells offers a unique opportunity to overcome these obstacles. By expanding and differentiating iPS cells, it is possible to generate large numbers of functional neurons in vitro, which can then be used to study the disease of the donating patient. Here, we provide an overview of human stem cell models of neurodegeneration using iPS cells from patients with Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington’s disease, spinal muscular atrophy and other neurodegenerative diseases. In addition, we describe how further refinements of reprogramming technology resulted in the generation of patient-specific induced neurons, which have also been used to model neurodegenerative changes in vitro.     

Composite low affinity interactions dictate recognition of the cyclin-dependent kinase inhibitor Sic1 by the SCFCdc4 ubiquitin ligase

The ubiquitin ligase SCF(Cdc4) (Skp1/Cul1/F-box protein) recognizes its substrate, the cyclin-dependent kinase inhibitor Sic1, in a multisite phosphorylation-dependent manner. Although short diphosphorylated peptides derived from Sic1 can bind to Cdc4 with high affinity, through systematic mutagenesis and quantitative biophysical analysis we show that individually weak, dispersed Sic1 phospho sites engage Cdc4 in a dynamic equilibrium. The affinities of individual phosphoepitopes serve to tune the overall phosphorylation site threshold needed for efficient recognition. Notably, phosphoepitope affinity for Cdc4 is dramatically weakened in the context of full-length Sic1, demonstrating the importance of regional environment on binding interactions. The multisite nature of the Sic1-Cdc4 interaction confers cooperative dependence on kinase activity for Sic1 recognition and ubiquitination under equilibrium reaction conditions. Composite dynamic interactions of low affinity sites may be a general mechanism to establish phosphorylation thresholds in biological responses.     

Blood pressure and risk of cancer incidence and mortality in the Metabolic Syndrome and Cancer Project

Observational studies have shown inconsistent results for the association between blood pressure and cancer risk. We investigated the association in 7 cohorts from Norway, Austria, and Sweden. In total, 577799 adults with a mean age of 44 years were followed for, on average, 12 years. Incident cancers were 22184 in men and 14744 in women, and cancer deaths were 8724 and 4525, respectively. Cox regression was used to calculate hazard ratios of cancer per 10-mmHg increments of midblood pressure, which corresponded with 0.7 SDs and, for example, an increment of systolic/diastolic blood pressure of 130/80 to 142/88 mmHg. All of the models used age as the time scale and were adjusted for possible confounders, including body mass index and smoking status. In men, midblood pressure was positively related to total incident cancer (hazard ratio per 10 mmHg increment: 1.07 [95% CI: 1.04-1.09]) and to cancer of the oropharynx, colon, rectum, lung, bladder, kidney, malignant melanoma, and nonmelanoma skin cancer. In women, midblood pressure was not related to total incident cancer but was positively related to cancer of the liver, pancreas, cervix, uterine corpus, and malignant melanoma. A positive association was also found for cancer mortality, with HRs per 10-mmHg increment of 1.12 (95% CI: 1.08-1.15) for men and 1.06 (95% CI: 1.02-1.11) for women. These results suggest a small increased cancer risk overall in men with elevated blood pressure level and a higher risk for cancer death in men and women.     

Mid-Aortic Syndrome in a 3-Year-Old Girl Successfully Treated by Aorto�CAortic Grafting and Renal Artery Implantation into the Graft

Mid-aortic syndrome, an uncommon acquired or congenital condition characterized by segmental narrowing of the abdominal or distal descending thoracic aorta, is frequently accompanied by ostial stenosis of the aorta''s branches. If left untreated, it can result in life-threatening complications secondary to severe hypertension.We report the case of a 3-year-old girl with congenital mid-aortic syndrome, who was diagnosed by chance in the course of a viral illness, and whose high blood pressure values were first dismissed as inaccurate. Attempts to achieve medical or endovascular control of her hypertension were unsuccessful. She was thereafter successfully treated by aorto–aortic bypass grafting, resection of the stenotic segments of both renal arteries, and implantation of the patent arterial segments into the graft.Key words: Angioplasty, balloon; aorta, abdominal/abnormalities; aortic coarctation/etiology/surgery; arterial occlusive diseases/surgery; child; hypertension, renal/etiology/surgery; mid-aortic syndrome; reconstructive surgical procedures/methods; renal artery obstruction/surgeryMid-aortic syndrome, an uncommon condition characterized by segmental narrowing of the abdominal or distal descending thoracic aorta, is frequently accompanied by ostial stenosis of its branches.^1–5 It can be acquired or congenital. Acquired causes of mid-aortic syndrome include neurofibromatosis, fibromuscular dysplasia, retroperitoneal fibrosis, Williams syndrome, mucopolysaccharidosis, giant cell arteritis (Takayasu disease, temporal arteritis), and acquired insults in utero or in early life that result in developmental disorders of the growing aorta.^1–13 Congenital mid-aortic syndrome is caused by a developmental anomaly in the fusion and maturation of the paired embryonic dorsal aortas and typically manifests itself in young patients.^6,14–19 We report the case of a 3-year-old girl with congenital mid-aortic syndrome, who was diagnosed by chance in the course of a viral illness and in whom high blood pressure values had at first been dismissed as inaccurate. Attempts to achieve medical or endovascular control of her hypertension were unsuccessful, so she was treated surgically.     

Variability in Stroop Task Performance and Functional Activation among a Small Brain-Injured Group

This study evaluated the effects of moderate to severe brain injury on cognitive task performance and cortical activation. Five participants completed a Stroop task while undergoing functional magnetic resonance imaging (fMRI) at two time points post-injury. Results revealed activation within regions typically activated during a Stroop task (the region of interest: ROI), though variability among participants was evident. Regions outside of the ROI were activated among all participants, to a greater degree than was present within the ROIs. This finding may indicate that recruitment of outside regions was necessary for successful task completion at both time points, and may suggest functional plasticity in cognitive task completion.     

Homozygous dystroglycan mutation associated with a novel muscle–eye–brain disease-like phenotype with multicystic leucodystrophy

Defects in dystroglycan post-translational modification result in congenital muscular dystrophy with or without additional eye and brain involvement, are referred to as secondary dystroglycanopathies and have been associated with mutations in 11 different genes encoding glycosyltransferases or associated proteins. However, only one patient with a mutation in the dystroglycan encoding gene DAG1 itself has been described before. We here report a homozygous novel DAG1 missense mutation c.2006G>T predicted to result in the amino acid substitution p.Cys669Phe in the β-subunit of dystroglycan in two Libyan siblings. The affected girls presented with a severe muscle–eye–brain disease-like phenotype with distinct additional findings of macrocephaly and extended bilateral multicystic white matter disease, overlapping with the cerebral findings in patients with megalencephalic leucoencephalopathy with subcortical cysts. This novel clinical phenotype observed in our patients further expands the clinical spectrum of dystroglycanopathies and suggests a role of DAG1 not only for dystroglycanopathies but also for some forms of more extensive and multicystic leucodystrophy.