For the first time, scientists have revealed a mechanism underlying the cellular degeneration of upper motor neurons, a small group of neurons in the brain recently shown to play a major role in ALS pathology. ALS, or amyotrophic lateral sclerosis, is a fatal neuromuscular disorder marked by the degeneration of motor neurons, which causes muscle weakness and impaired speaking, swallowing and…
In the inconceivably vast and humbling unknown called “everything,” is a supreme inter-communication called, spirituality. The laws of life are written into every atom, molecule, and heartbeat. The clues to the great mystery are all around us! To understand the mysteries of life, you must look around and within. You will see patterns everywhere; patterns that seem to manifest themselves over and over again. These patterns exist intertwined within nature and man, bridging the gap between the enigma of self and the entire universe itself. You see them in spiraling galaxies and Mandelbrot fractals, and the logarithmic swirls of fossilized Ammonoidea — growing from the unknown to atoms, to molecules to solar systems, to galaxies to the furthest expanses of the universe, with origins and destinations unknown; just like us in birth and death. You see them in the similarities between tree branches, rivers and blood veins, the patterns of fingerprints like endoplasmic reticulum, or a black opal’s play of fire like the nebula of a supernova. Moon shots are like protoplasmic lurches, while simple thoughts and observations of the nature around us take us beyond the unknown. The clues to the great mystery are all around us and deep within us. We are all immersed in the sweet law of unfolding mystery called life. There is a way to flow and cooperate with universal laws that can be beautiful and kind. When we are in sync with this flow, its power moves us like a mighty yet gentle guiding hand. The flow of spiritual connectedness and oneness with life will dwell in you if your heart and mind is open and innocent. If you are pure in intention and in alignment with beauty and love, in body and mind, the highest levels of your spiritual self will subsume your weaknesses. Spirituality will take you like love; it seduces you from contemplation to completeness.
— Bryant McGill
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(This passage is from the SR book, but I post all my writings freely as a gift for those who cannot afford them. If these writings have benefited you, please kindly leave a review at bryantmcgill.com/sr-amazon)
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Cerebral venous sinus thrombosis (CVST) is a rare form of stroke. The role of endoplasmic reticulum (ER) stress markers is well documented in arterial stroke but has not been evaluated in venous stroke. The present study has been undertaken to investigate the role of ER stress in rodent model of CVST. For inducing CVST, a cranial window was made to expose superior sagittal sinus (SSS). A strip of filter paper soaked with 40% ferric chloride was applied on exposed cranial window while in sham operated control 0.9% saline was used. Clinical evaluations were done on day 1, 2, and 7 for neurological deficit. Rota rod test and brain infarction volume were also measured. Brain tissue was collected from infarcted portion for further analysis using real time polymerase chain reaction and western blot technique for ER stress markers. Augmented expression of ER stress markers and up regulation of apoptotic genes were found in infarcted tissue. These markers improved on day 7. It is concluded that ER markers are up regulated at an early stage of CVST and may be important in pathophysiology.
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Oxidative stress involving changes in Nrf2 and ER stress in early stages of Alzheimer’s disease.
Biochim Biophys Acta. 2015 Jul;1852(7):1428-41
Authors: Mota SI, Costa RO, Ferreira IL, Santana I, Caldeira GL, Padovano C, Fonseca AC, Baldeiras I, Cunha C, Letra L, Oliveira CR, Pereira CM, Rego AC
Oxidative stress and endoplasmic reticulum (ER) stress have been associated with Alzheimer’s disease (AD) progression. In this study we analyzed whether oxidative stress involving changes in Nrf2 and ER stress may constitute early events in AD pathogenesis by using human peripheral blood cells and an AD transgenic mouse model at different disease stages. Increased oxidative stress and increased phosphorylated Nrf2 (p(Ser40)Nrf2) were observed in human peripheral blood mononuclear cells (PBMCs) isolated from individuals with mild cognitive impairment (MCI). Moreover, we observed impaired ER Ca2+ homeostasis and increased ER stress markers in PBMCs from MCI individuals and mild AD patients. Evidence of early oxidative stress defense mechanisms in AD was substantiated by increased p(Ser40)Nrf2 in 3month-old 3xTg-AD male mice PBMCs, and also with increased nuclear Nrf2 levels in brain cortex. However, SOD1 protein levels were decreased in human MCI PBMCs and in 3xTg-AD mice brain cortex; the latter further correlated with reduced SOD1 mRNA levels. Increased ER stress was also detected in the brain cortex of young female and old male 3xTg-AD mice. We demonstrate oxidative stress and early Nrf2 activation in AD human and mouse models, which fails to regulate some of its targets, leading to repressed expression of antioxidant defenses (e.g., SOD-1), and extending to ER stress. Results suggest markers of prodromal AD linked to oxidative stress associated with Nrf2 activation and ER stress that may be followed in human peripheral blood mononuclear cells.
Huntingtin is required for ER-to-Golgi transport and for secretory vesicle fusion at the plasma membrane.
Dis Model Mech. 2014 Dec;7(12):1335-40
Authors: Brandstaetter H, Kruppa AJ, Buss F
Huntingtin is a large membrane-associated scaffolding protein that associates with endocytic and exocytic vesicles and modulates their trafficking along cytoskeletal tracks. Although the progression of Huntington’s disease is linked to toxic accumulation of mutant huntingtin protein, loss of wild-type huntingtin function might also contribute to neuronal cell death, but its precise function is not well understood. Therefore, we investigated the molecular role of huntingtin in exocytosis and observed that huntingtin knockdown in HeLa cells causes a delay in endoplasmic reticulum (ER)-to-Golgi transport and a reduction in the number of cargo vesicles leaving the trans-Golgi network. In addition, we found that huntingtin is required for secretory vesicle fusion at the plasma membrane. Similar defects in the early exocytic pathway were observed in primary fibroblasts from homozygous Htt(140Q/140Q) knock-in mice, which have the expansion inserted into the mouse huntingtin gene so lack wild-type huntingtin expression. Interestingly, heterozygous fibroblasts from a Huntington’s disease patient with a 180Q expansion displayed no obvious defects in the early secretory pathway. Thus, our results highlight the requirement for wild-type huntingtin at distinct steps along the secretory pathway.
A systematic immunoprecipitation approach reinforces the concept of common conformational alterations in amyotrophic lateral sclerosis-linked SOD1 mutants.
Neurobiol Dis. 2015 Aug 18;
Authors: Fujisawa T, Yamaguchi N, Kadowaki H, Tsukamoto Y, Tsuburaya N, Tsubota A, Takahashi H, Naguro I, Takahashi Y, Goto J, Tsuji S, Nishitoh H, Homma K, Ichijo H
Mutations in the Cu, Zn superoxide dismutase (SOD1) gene are one of the causative agents of amyotrophic lateral sclerosis (ALS). Although more than 100 different mutations in SOD1 have been identified, it is unclear whether all the mutations are pathogenic or just single nucleotide polymorphisms (SNPs) unrelated to the disease. Our previous systematic analysis found that all pathogenic SOD1 mutants (SOD1(mut)) have a common property, namely, an association with Derlin-1, a component of the endoplasmic reticulum-associated degradation machinery. For the proposed mechanism, we found that most pathogenic SOD1(mut) have a constitutively exposed Derlin-1-binding region (DBR), which is concealed in wild-type SOD1 (SOD1(WT)). Moreover, we generated MS785, a monoclonal antibody against DBR. MS785 distinguished most ALS-causative SOD1(mut) from both SOD1(WT) and non-toxic SOD1(mut). However, MS785 could not recognize SOD1(mut) that has mutations in the MS785 epitope region. Here, we developed a new diagnostic antibody, which could compensate for this shortcoming of MS785. We hypothesized that in ALS-causative SOD1(mut), the DBR-neighboring region [SOD1(30-40)] may also be exposed. We then generated MS27, a monoclonal antibody against SOD1(30-40). We found that MS27 could distinguish SOD1(WT) from the pathogenic SOD1(mut), which has mutations in the MS785 epitope region. Moreover, all pathogenic SOD1(mut), without exception, were immunoprecipitated with a combination of MS785 and MS27. The MS785-MS27 combination could be developed as a novel mechanism-based biomarker for the diagnosis of ALS.