Congenital myasthenic syndromes (CMS) are genetic disorders characterised by impaired neuromuscular transmission. This review provides an overview on CMS and highlights recent advances in the field, ...including novel CMS causative genes and improved therapeutic strategies. CMS due to mutations in
and
, impairing the synthesis and recycling of acetylcholine, have recently been described. In addition, a novel group of CMS due to mutations in
,
,
, and
encoding molecules implicated in synaptic vesicles exocytosis has been characterised. The increasing number of presynaptic CMS exhibiting CNS manifestations along with neuromuscular weakness demonstrate that the myasthenia can be only a small part of a much more extensive disease phenotype. Moreover, the spectrum of glycosylation abnormalities has been increased with the report that
mutations can cause CMS, thus bridging myasthenic disorders with dystroglycanopathies. Finally, the discovery of
mutations and laminin α5 deficiency has helped to draw attention to the role of extracellular matrix proteins for the formation and maintenance of muscle endplates. The benefit of β2-adrenergic agonists alone or combined with pyridostigmine or 3,4-Dyaminopiridine is increasingly being reported for different subtypes of CMS including AChR-deficiency and glycosylation abnormalities, thus expanding the therapeutic repertoire available.
IMPORTANCE: Cell-based assays (CBAs) were shown to improve detection of acetylcholine receptor (AChR) antibodies in patients with myasthenia gravis (MG). Herein, we asked whether these assays were ...able to help determine the diagnosis in patients studied in routine clinical practice. OBJECTIVES: To determine the diagnostic usefulness of CBAs in the diagnosis of MG and to compare the clinical features of patients with antibodies only to clustered AChRs with those of patients with seronegative MG (SNMG). DESIGN, SETTING, AND PARTICIPANTS: All patients with clinical suspicion of MG who were seen within the Division of Clinical Neurology at the John Radcliffe Hospital in Oxford, England, between November 1, 2009, and November 30, 2013. Their serum antibodies and clinical features were studied. EXPOSURES: Radioimmunoprecipitation assay (RIPA) and CBA were used to test for standard AChR antibodies and antibodies to clustered AChRs in 138 patients. All available samples from patients with SNMG were retrospectively tested for lipoprotein receptor–related protein 4 (LRP4) antibodies. MAIN OUTCOMES AND MEASURES: Demographic, clinical, neurophysiological, and laboratory data. RESULTS: In total, 138 patients were tested for antibodies to clustered AChRs, and 42 had a final diagnosis of MG. The clustered AChR CBA detected antibodies in 38.1% (16 of 42) of RIPA-negative patients with MG with 100% specificity. All patients with SNMG who were tested for LRP4 antibodies (21 of 26) were negative by CBA. Compared with patients with SNMG, patients with antibodies only to clustered AChRs had frequent prepubertal onset (62.5% median age, 6 years; age range, 1-52 years vs 11.5% median age, 38 years; age range, 2-72 years, P ≤ .05), high prevalence of ocular MG (62.5% vs 42.3%), milder disease severity with less bulbar involvement (25.0% vs 46.2%), and absence of respiratory symptoms (0% vs 23.1%). Response to treatment and prognosis was good, with a reduced need for thymectomy (6.3% vs 19.2%) and a high proportion of patients going into remission (50.0% vs 8.3%, P ≤ .05). These observations also apply to the classic AChR MG phenotype seen in large series. CONCLUSIONS AND RELEVANCE: Cell-based assay is a useful procedure in the routine diagnosis of RIPA-negative MG, particularly in children. Patients with antibodies only to clustered AChRs appear to be younger and have milder disease than other patients with MG. These observations will have implications in planning treatment.
The neuromuscular junction (NMJ) is a highly specialized synapse between a motor neuron nerve terminal and its muscle fiber that are responsible for converting electrical impulses generated by the ...motor neuron into electrical activity in the muscle fibers. On arrival of the motor nerve action potential, calcium enters the presynaptic terminal, which leads to the release of the neurotransmitter acetylcholine (ACh). ACh crosses the synaptic gap and binds to ACh receptors (AChRs) tightly clustered on the surface of the muscle fiber; this leads to the endplate potential which initiates the muscle action potential that results in muscle contraction. This is a simplified version of the events in neuromuscular transmission that take place within milliseconds, and are dependent on a tiny but highly structured NMJ. Much of this review is devoted to describing in more detail the development, maturation, maintenance and regeneration of the NMJ, but first we describe briefly the most important molecules involved and the conditions that affect their numbers and function. Most important clinically worldwide, are myasthenia gravis (MG), the Lambert-Eaton myasthenic syndrome (LEMS) and congenital myasthenic syndromes (CMS), each of which causes specific molecular defects. In addition, we mention the neurotoxins from bacteria, snakes and many other species that interfere with neuromuscular transmission and cause potentially fatal diseases, but have also provided useful probes for investigating neuromuscular transmission. There are also changes in NMJ structure and function in motor neuron disease, spinal muscle atrophy and sarcopenia that are likely to be secondary but might provide treatment targets. The NMJ is one of the best studied and most disease-prone synapses in the nervous system and it is amenable to
and
investigation and to systemic therapies that can help restore normal function.
A systematic classification and accepted nomenclature of neuron types is much needed but is currently lacking. This article describes a possible taxonomical solution for classifying GABAergic ...interneurons of the cerebral cortex based on a novel, web-based interactive system that allows experts to classify neurons with pre-determined criteria. Using Bayesian analysis and clustering algorithms on the resulting data, we investigated the suitability of several anatomical terms and neuron names for cortical GABAergic interneurons. Moreover, we show that supervised classification models could automatically categorize interneurons in agreement with experts' assignments. These results demonstrate a practical and objective approach to the naming, characterization and classification of neurons based on community consensus.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Anti-inflammatory strategies are proposed to have beneficial effects in Alzheimer’s disease. To explore how anti-inflammatory cytokine signaling affects Aβ pathology, we investigated the effects of ...adeno-associated virus (AAV2/1)-mediated expression of Interleukin (IL)-10 in the brains of APP transgenic mouse models. IL-10 expression resulted in increased Aβ accumulation and impaired memory in APP mice. A focused transcriptome analysis revealed changes consistent with enhanced IL-10 signaling and increased ApoE expression in IL-10-expressing APP mice. ApoE protein was selectively increased in the plaque-associated insoluble cellular fraction, likely because of direct interaction with aggregated Aβ in the IL-10-expressing APP mice. Ex vivo studies also show that IL-10 and ApoE can individually impair glial Aβ phagocytosis. Our observations that IL-10 has an unexpected negative effect on Aβ proteostasis and cognition in APP mouse models demonstrate the complex interplay between innate immunity and proteostasis in neurodegenerative diseases, an interaction we call immunoproteostasis.
•The anti-inflammatory cytokine, IL-10, increases Aβ accumulation in APP mouse brain•IL-10 exacerbates memory impairment in APP mice and reduces synaptic proteins•IL-10 increases ApoE, which, by binding aggregated Aβ, is sequestered in plaques•IL-10 and ApoE suppress microglial Aβ phagocytosis in vitro
Chakrabarty et al. show that Interleukin-10 increases Aβ plaque deposition and impairs cognition in APP mice. This is mechanistically linked to decreased microglial Aβ phagocytosis and increased ApoE expression and sequestration in plaques, consistent with ApoE’s role as a pathological chaperone.
Congenital myasthenic syndromes (CMS) are a group of heterogeneous inherited disorders caused by mutations in genes encoding proteins essential for the integrity of neuromuscular transmission. This ...review updates the reader on the new mutations of known CMS genes, new causative genes and the treatment strategies for these increasingly heterogeneous disorders. It also provides a brief summary of the congenital myopathies with myasthenic features.
The discovery of causative genes encoding for ubiquitously expressed and extrajunctional molecules has changed our previous view of congenital myasthenia. Mutations associated with the N-glycosylation pathway and in the family of serine peptidases have shown that abnormalities in the post-translational modification of proteins can produce defects at the human neuromuscular junction. However, mutations in lipoprotein-like receptor 4, a long-time candidate gene for congenital myasthenia, have now been described and a new pathogenic splicing mutation in the nonfunctional exon of CHRNA1 has been reported. The use of salbutamol and ephedrine alone or combined with pyridostigmine or 3,4-DAP is increasingly being reported in different CMS subtypes with significant benefit.
Recent studies of the CMS illustrate the increasing complexity of the genetics, pathophysiological mechanisms and therapy of impaired synaptic transmission at the neuromuscular junction.
Tetrasubstituted stereogenic carbon centers bearing a nitrogen substituent represent important motifs in medicinal chemistry and natural products; therefore, the development of efficient methods for ...the stereoselective synthesis of this class of compounds continues to be an important problem. This article describes stereoconvergent Henry reactions of γ,γ-disubstituted nitroalkanes to deliver highly functionalized building blocks containing up to five contiguous stereogenic centers including a fully substituted N-asymmetric center. Henry reactions of higher order nitroalkanes are often characterized by their reversibility and minimal accompanying thermodynamic stereocontrol. In contrast, mechanistic studies for the present case suggest a scenario in which reversibility is productively leveraged through crystallization-based stereocontrol, thereby enabling the efficient sequential π-additions of readily accessible starting materials to assemble complex acyclic stereoarrays.
A bifunctional iminophosphorane (BIMP)-catalyzed method for the synthesis of densely functionalized cyclohexanols establishes five contiguous stereocenters (diastereoselection up to >20:1, ...enantioselectivity up to >99:1) in a Michael/aldol domino reaction between trisubstituted electrophilic alkenes and γ-nitroketones. Mechanistic studies suggest a scenario in which stereoconvergency is achieved by kinetically controlled cyclization after the initial diastereodivergent Michael addition. Diastereoconvergency during cyclization is shown to result from Curtin–Hammett kinetics, a finding that contrasts the crystallization-driven stereoconvergency previously reported in similar systems. Despite the change in the stereocontrol mechanism, the operational attributes remain attractive, with the crystalline products typically isolated in analytically pure form upon filtration of the reaction mixture.
While the unique metabolic activities of malignant tissues as potential targets for cancer therapeutics has been the subject of several recent reviews, the role of cholesterol metabolism in this ...context is yet to be fully explored. Cholesterol is an essential component of mammalian cell membranes as well as a precursor of bile acids and steroid hormones. The hypothesis that cancer cells need excess cholesterol and intermediates of the cholesterol biosynthesis pathway to maintain a high level of proliferation is well accepted, however the mechanisms by which malignant cells and tissues reprogram cholesterol synthesis, uptake and efflux are yet to be fully elucidated as potential therapeutic targets. High and low density plasma lipoproteins are the likely major suppliers of cholesterol to cancer cells and tumors, potentially via receptor mediated mechanisms. This review is primarily focused on the role(s) of lipoproteins in carcinogenesis, and their future roles as drug delivery vehicles for targeted cancer chemotherapy.
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