Astroglia in Leukodystrophies.

Astroglia in Leukodystrophies. Adv Exp Med Biol. 2019;1175:199-225 Authors: Jorge MS, Bugiani M Abstract Leukodystrophies are genetically determined disorders affecting the white matter of the central nervous system. The combination of MRI pattern recognition and next-generation sequencing for the definition of novel disease entities has recently demonstrated that many leukodystrophies are due to the primary involvement and/or mutations in genes selectively expressed by cell types other than the oligodendrocytes, the myelin-forming cells in the brain. This has led to a new definition of leukodystrophies as genetic white matter disorders resulting from the involvement of any white matter structural component. As a result, the research has shifted its main focus from oligodendrocytes to other types of neuroglia. Astrocytes are the housekeeping cells of the nervous system, responsible for maintaining homeostasis and normal brain physiology and to orchestrate repair upon injury. Several lines of evidence show that astrocytic interactions with the other white matter cellular constituents play a primary pathophysiologic role in many leukodystrophies. These are thus now classified as astrocytopathies. This chapter addresses how the crosstalk between astrocytes, other glial cells, axons and non-neural cells are essential for the integrity and maintenance of the white matter in health. It also addresses the current knowledge of the cellular pathomechanisms of astr...
Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research

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Publication date: Available online 12 July 2019Source: The Lancet NeurologyAuthor(s): Marjo S van der Knaap, Raphael Schiffmann, Fanny Mochel, Nicole I WolfSummaryLeukodystrophies comprise a large group of rare genetic disorders primarily affecting CNS white matter. Historically, the diagnostic process was slow and patient prognosis regarded as poor because curative treatment was only available for very few leukodystrophies in early stages of the disease. Whole-exome sequencing has both greatly increased the number of known leukodystrophies and improved diagnosis. Whether MRI keeps its central place in diagnosis and what t...
Source: The Lancet Neurology - Category: Neurology Source Type: research
Reena Goswami1, Gayatri Subramanian2, Liliya Silayeva1, Isabelle Newkirk1, Deborah Doctor1, Karan Chawla2, Saurabh Chattopadhyay2, Dhyan Chandra3, Nageswararao Chilukuri1 and Venkaiah Betapudi1,4* 1Neuroscience Branch, Research Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen, MD, United States 2Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States 3Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States 4Department of Physiology and Biophysics, Case Western Reserve University, Clev...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
AbstractPelizaeus –Merzbacher disease (PMD) is an untreatable and fatal leukodystrophy. In a model of PMD with perturbed blood–brain barrier integrity, cholesterol supplementation promotes myelin membrane growth. Here, we show that in contrast to the mouse model, dietary cholesterol in two PMD patients did not le ad to a major advancement of hypomyelination, potentially because the intact blood–brain barrier precludes its entry into the CNS. We therefore turned to a PMD mouse model with preserved blood–brain barrier integrity and show that a high-fat/low-carbohydrate ketogenic diet restored oligoden...
Source: Acta Neuropathologica - Category: Neurology Source Type: research
Cerebral leukodystrophy is an X-linked peroxisomal disease characterized by mutations in the ABCD1 gene, resulting in the lack of very long chain fatty acid (VLCFA) transport into peroxisomes. Resultant VLCFA build up in the blood and tissues leads to adrenal gland insufficiency in 95% of boys and an inflammatory cerebral demyelinating process in 40% of patients, which is progressive and most often fatal (cALD). A key clinical feature of cALD is disruption of the blood brain barrier (BBB) illustrated by gadolinium (gad) contrast enhancement on brain MRI at diagnosis and as an indicator of “active” cerebral disease.
Source: Biology of Blood and Marrow Transplantation - Category: Hematology Authors: Tags: 117 Source Type: research
In conclusion, we found a gradient of increasing blood pressure with higher levels of BMI. The fact that this gradient is present even in the fully adjusted analyses suggests that BMI may cause a direct effect on blood pressure, independent of other clinical risk factors. PRRX1 as a Possible Point of Control for Remyelination https://www.fightaging.org/archives/2018/12/prrx1-as-a-possible-point-of-control-for-remyelination/ Researchers here outline what is possibly a new point of intervention in the processes that maintain the myelin sheath that wraps nerves. This sheath is vital to the correct operatio...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Cerebral leukodystrophy is an X-linked peroxisomal disease characterized by mutations in the ABCD1 gene, resulting in the lack of very long chain fatty acid (VLCFA) transport into peroxisomes. Resultant VLCFA build up in the blood and tissues leads to adrenal gland insufficiency in 95% of boys and a progressive inflammatory cerebral demyelinating process in 40% of patients, which is progressive and most often fatal (cALD). Only hematopoietic stem cell transplant (HSCT) has been shown to halt cerebral disease progression. A key clinical feature of cALD is disruption of the blood brain barrier (BBB) illustrated by gadolinium...
Source: Blood - Category: Hematology Authors: Tags: 732. Clinical Allogeneic Transplantation: Results: Poster III Source Type: research
We present a pedigree with autosomal dominant renal TMA and chronic kidney disease found to have a carboxy-terminal frameshift TREX1 variant. Although symptomatic brain and retinal microangiopathy is known to associate with carboxy-terminal TREX1 mutations, this report describes a carboxy-terminal TREX1 frameshift variant causing predominant renal TMA. These findings underscore the clinical importance of recognizing TREX1 mutations as a cause of renal TMA. This case demonstrates the value of whole-exome sequencing in unsolved TMA.
Source: American Journal of Kidney Diseases - Category: Urology & Nephrology Source Type: research
We present a pedigree with autosomal dominant renal TMA and chronic kidney disease found to have a carboxy-terminal frameshift TREX1 variant. Although symptomatic brain and retinal microangiopathy is known to associate with carboxy-terminal TREX1 mutations, this report describes a carboxy-terminal TREX1 frameshift variant causing predominant renal TMA. These findings underscore the clinical importance of recognizing TREX1 mutations as a cause of renal TMA. This case demonstrates the value of whole-exome sequencing in unsolved TMA.
Source: American Journal of Kidney Diseases - Category: Urology & Nephrology Source Type: research
We present two additional unrelated cases, and provide a more complete clinical description that includes hyperglycinemia, leukodystrophy of the brainstem with longitudinally extensive spinal cord involvement, and mtDNA deficiency. Additionally, we characterize the role of ISCA2 in mitochondrial bioenergetics and Fe–S cluster assembly using subject cells and ISCA2 cellular knockdown models. Loss of ISCA2 diminished mitochondrial membrane potential, the mitochondrial network, basal and maximal respiration, ATP production, and activity of ETC complexes II and IV. We specifically tested the impact of loss of ISCA2 on 2F...
Source: Human Mutation - Category: Genetics & Stem Cells Authors: Tags: RESEARCH ARTICLE Source Type: research
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Source: Human Mutation - Category: Genetics & Stem Cells Authors: Tags: RESEARCH ARTICLE Source Type: research
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