45 research outputs found
Mapping interactions with the chaperone network reveals factors that protect against tau aggregation.
A network of molecular chaperones is known to bind proteins ('clients') and balance their folding, function and turnover. However, it is often unclear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein-aggregation diseases. Here, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ~30 purified chaperones and ~20 disease-associated tau variants (~600 combinations). From this large-scale analysis, we identified human DnaJA2 as an unexpected, but potent, inhibitor of tau aggregation. DnaJA2 levels were correlated with tau pathology in human brains, supporting the idea that it is an important regulator of tau homeostasis. Of note, we found that some disease-associated tau variants were relatively immune to interactions with chaperones, suggesting a model in which avoiding physical recognition by chaperone networks may contribute to disease
Periconceptional Maternal Folic Acid Use of 400 µg per Day Is Related to Increased Methylation of the IGF2 Gene in the Very Young Child
Background: Countries worldwide recommend women planning pregnancy to use daily 400 mg of synthetic folic acid in the periconceptional period to prevent birth defects in children. The underlying mechanisms of this preventive effect are not clear, however, epigenetic modulation of growth processes by folic acid is hypothesized. Here, we investigated whether periconceptional maternal folic acid use and markers of global DNA methylation potential (S-adenosylmethionine and S-adenosylhomocysteine blood levels) in mothers and children affect methylation of the insulin-like growth factor 2 gene differentially methylation region (IGF2 DMR) in the child. Moreover, we tested whether the methylation of the IGF2 DMR was independently associated with birth weight. Methodology/Principal Findings: IGF2 DMR methylation in 120 children aged 17 months (SD 0.3) of whom 86 mothers had used and 34 had not used folic acid periconceptionally were studied. Methylation was measured of 5 CpG dinucleotides covering the DMR using a mass spectrometry-based method. Children of mother who used folic acid had a 4.5% higher methylation of the IGF2 DMR than children who were not exposed to folic acid (49.5% vs. 47.4%; p = 0.014). IGF2 DMR methylation of the children also was associated with the S-adenosylmethionine blood level of the mother but not of the child (+1.7% methylation per SD S-adenosylmethionine; p = 0.037). Finally, we observed an inverse independent association between IGF2 DMR methylation and birth weight (-1.7% methylation per SD birthweight; p = 0.034). Conclusions: Periconceptional folic acid use is associated with epigenetic changes in IGF2 in the child that may affect intrauterine programming of growth and development with consequences for health and disease throughout life. These results indicate plasticity of IGF2 methylation by periconceptional folic acid use
CXCR6, a Newly Defined Biomarker of Tissue-Specific Stem Cell Asymmetric Self-Renewal, Identifies More Aggressive Human Melanoma Cancer Stem Cells
Background: A fundamental problem in cancer research is identifying the cell
type that is capable of sustaining neoplastic growth and its origin from normal
tissue cells. Recent investigations of a variety of tumor types have shown that
phenotypically identifiable and isolable subfractions of cells possess the
tumor-forming ability. In the present paper, using two lineage-related human
melanoma cell lines, primary melanoma line IGR39 and its metastatic derivative
line IGR37, two main observations are reported. The first one is the first
phenotypic evidence to support the origin of melanoma cancer stem cells (CSCs)
from mutated tissue-specific stem cells; and the second one is the
identification of a more aggressive subpopulation of CSCs in melanoma that are
CXCR6+. Conclusions/Significance: The association of a more aggressive tumor
phenotype with asymmetric self-renewal phenotype reveals a previously
unrecognized aspect of tumor cell physiology. Namely, the retention of some
tissue-specific stem cell attributes, like the ability to asymmetrically
self-renew, impacts the natural history of human tumor development. Knowledge
of this new aspect of tumor development and progression may provide new targets
for cancer prevention and treatment
Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases
The production of peroxide and superoxide is an inevitable consequence of
aerobic metabolism, and while these particular "reactive oxygen species" (ROSs)
can exhibit a number of biological effects, they are not of themselves
excessively reactive and thus they are not especially damaging at physiological
concentrations. However, their reactions with poorly liganded iron species can
lead to the catalytic production of the very reactive and dangerous hydroxyl
radical, which is exceptionally damaging, and a major cause of chronic
inflammation. We review the considerable and wide-ranging evidence for the
involvement of this combination of (su)peroxide and poorly liganded iron in a
large number of physiological and indeed pathological processes and
inflammatory disorders, especially those involving the progressive degradation
of cellular and organismal performance. These diseases share a great many
similarities and thus might be considered to have a common cause (i.e.
iron-catalysed free radical and especially hydroxyl radical generation). The
studies reviewed include those focused on a series of cardiovascular, metabolic
and neurological diseases, where iron can be found at the sites of plaques and
lesions, as well as studies showing the significance of iron to aging and
longevity. The effective chelation of iron by natural or synthetic ligands is
thus of major physiological (and potentially therapeutic) importance. As
systems properties, we need to recognise that physiological observables have
multiple molecular causes, and studying them in isolation leads to inconsistent
patterns of apparent causality when it is the simultaneous combination of
multiple factors that is responsible. This explains, for instance, the
decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference
Latent analysis of unmodified biomolecules and their complexes in solution with attomole detection sensitivity
The study of biomolecular interactions is central to an understanding of function, malfunction and therapeutic modulation of biological systems, yet often involves a compromise between sensitivity and accuracy. Many conventional analytical steps and the procedures required to facilitate sensitive detection, such as the incorporation of chemical labels, are prone to perturb the complexes under observation. Here we present a 'latent' analysis approach that uses chemical and microfluidic tools to reveal, through highly sensitive detection of a labelled system, the behaviour of the physiologically relevant unlabelled system. We implement this strategy in a native microfluidic diffusional sizing platform, allowing us to achieve detection sensitivity at the attomole level, determine the hydrodynamic radii of biomolecules that vary by over three orders of magnitude in molecular weight, and study heterogeneous mixtures. We illustrate these key advantages by characterizing a complex of an antibody domain in the solution phase and under physiologically relevant conditions.We would like to thank the ERC, BBSRC, Wellcome Trust, Newman Foundation, Winston Churchill Foundation, and Elan Pharmaceuticals for financial support. E.D.G was supported by the MRC (G1002272)
A new era for understanding amyloid structures and disease
The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. The accumulation and deposition of amyloid fibrils, collectively known as amyloidosis, is associated with many pathological conditions that can be associated with ageing, such as Alzheimer disease, Parkinson disease, type II diabetes and dialysis-related amyloidosis. However, elucidation of the atomic structure of amyloid fibrils formed from their intact protein precursors and how fibril formation relates to disease has remained elusive. Recent advances in structural biology techniques, including cryo-electron microscopy and solid-state NMR spectroscopy, have finally broken this impasse. The first near-atomic-resolution structures of amyloid fibrils formed in vitro, seeded from plaque material and analysed directly ex vivo are now available. The results reveal cross-β structures that are far more intricate than anticipated. Here, we describe these structures, highlighting their similarities and differences, and the basis for their toxicity. We discuss how amyloid structure may affect the ability of fibrils to spread to different sites in the cell and between organisms in a prion-like manner, along with their roles in disease. These molecular insights will aid in understanding the development and spread of amyloid diseases and are inspiring new strategies for therapeutic intervention
Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes
Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues
Endoscopic-assisted maxillectomy: Operative technique and control of surgical margins
When amenable to radical excision, cancer involving the maxilla is typically treated with maxillectomy followed by adjuvant therapy. Posterior tumor extension beyond the maxillary box leads to the invasion of complex areas, where achieving clear margins may be challenging.Background: When amenable to radical excision, cancer involving the maxilla is typically treated with maxillectomy followed by adjuvant therapy. Posterior tumor extension beyond the maxillary box leads to the invasion of complex areas, where achieving clear margins may be challenging. Methods: Patients undergoing endoscopic-assisted maxillectomy for nasoethmoidal, maxillary, or hard palate cancer between 2007 and 2017 were included in the study. Surgical technique, margin status, and recurrences were analyzed. Extension of posterior resection was classified in 3 types (type 1: resection of the pterygopalatine fossa; type 2: resection of the pterygoid plates and related muscles; type 3: resection of the upper parapharyngeal space). The analysis of putative risk factors for involvement of margins and local recurrence was performed with special focus on the posterior and medial margin. Results: The study included 79 patients (75 with available follow-up; mean: 20.6 months, range: 6\u2013101 months), 37 (46.8%) of whom underwent type 1 resection, 34 (43.0%) type 2, and 8 (10.1%) type 3. According to pT category, 57 (72.2%) tumors were classified as T4a/T4b. Posterior and medial clear margins were achieved in 76/79 (96.2%) and 75/79 (94.9%) patients, respectively. T4b category, extension to the ethmoid, sphenoid sinus, pterygoid process, orbital cavity, and premaxillary tissues were significantly associated with a higher rate of margin involvement. None of the factors was significantly associated with medial margin involvement. Conclusion: Endoscopic-assisted maxillectomy combines several refinements including the facilitated detachment of the maxilla from the skull base and precise delineation of the posterior and medial margins of resection