Oligodendrocyte Death in Pelizaeus-Merzbacher Disease Is Rescued by Iron Chelation.

Oligodendrocyte Death in Pelizaeus-Merzbacher Disease Is Rescued by Iron Chelation. Cell Stem Cell. 2019 Oct 03;25(4):531-541.e6 Authors: Nobuta H, Yang N, Ng YH, Marro SG, Sabeur K, Chavali M, Stockley JH, Killilea DW, Walter PB, Zhao C, Huie P, Goldman SA, Kriegstein AR, Franklin RJM, Rowitch DH, Wernig M Abstract Pelizaeus-Merzbacher disease (PMD) is an X-linked leukodystrophy caused by mutations in Proteolipid Protein 1 (PLP1), encoding a major myelin protein, resulting in profound developmental delay and early lethality. Previous work showed involvement of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways, but poor PLP1 genotype-phenotype associations suggest additional pathogenetic mechanisms. Using induced pluripotent stem cell (iPSC) and gene-correction, we show that patient-derived oligodendrocytes can develop to the pre-myelinating stage, but subsequently undergo cell death. Mutant oligodendrocytes demonstrated key hallmarks of ferroptosis including lipid peroxidation, abnormal iron metabolism, and hypersensitivity to free iron. Iron chelation rescued mutant oligodendrocyte apoptosis, survival, and differentiationin vitro, and post-transplantation in vivo. Finally, systemic treatment of Plp1 mutant Jimpy mice with deferiprone, a small molecule iron chelator, reduced oligodendrocyte apoptosis and enabled myelin formation. Thus, oligodendrocyte iron-induced cell death and myelination is rescued by iron chela...
Source: Cell Stem Cell - Category: Stem Cells Authors: Tags: Cell Stem Cell Source Type: research

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The leukodystrophies are a heterogeneous group of inherited disorders that disrupt myelination in the central nervous system (CNS) and may also involve the peripheral nervous system. The onset and severity of symptoms differ between diseases and may correlate with genetic mutation(s). In the most severe forms, affected individuals experience rapid, progressive, and ultimately fatal neurologic symptoms. Without newborn screening (NBS) or a known family history, the diagnosis of the index case in a family is usually delayed until symptoms are present and progress to a stage where treatment with transplantation is no longer p...
Source: Biology of Blood and Marrow Transplantation - Category: Hematology Authors: Source Type: research
Publication date: Available online 1 August 2019Source: Stem Cell ReportsAuthor(s): Nalin Gupta, Roland G. Henry, Sang-Mo Kang, Jonathan Strober, Daniel A. Lim, Tamara Ryan, Rachel Perry, Jody Farrell, Mary Ulman, Raja Rajalingam, Allyson Gage, Stephen L. Huhn, A. James Barkovich, David H. RowitchSummaryFour boys with Pelizaeus-Merzbacher disease, an X-linked leukodystrophy, underwent transplantation with human allogeneic central nervous system stem cells (HuCNS-SC). Subsequently, all subjects were followed for an additional 4 years in this separate follow-up study to evaluate safety, neurologic function, magnetic resonanc...
Source: Stem Cell Reports - Category: Stem Cells Source Type: research
CONCLUSIONS: Although the complication rate for patients with Krabbe disease and metachromatic leukodystrophy is higher than the general population, most complications were mild and self-limiting. These results suggest that, in experienced hands, general anesthesia is well tolerated in most children. Findings show that the Neurodevelopment in Rare Disorders classification system is a better indicator for assessing complication risk in patients with Krabbe and metachromatic leukodystrophy than American Society of Anesthesiologists Physical Status. PMID: 31359511 [PubMed - as supplied by publisher]
Source: Paediatric Anaesthesia - Category: Anesthesiology Authors: Tags: Paediatr Anaesth 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
Publication date: Available online 21 February 2019Source: Stem Cell ReportsAuthor(s): Stephanie Dooves, Prisca S. Leferink, Sander Krabbenborg, Nicole Breeuwsma, Saskia Bots, Anne E.J. Hillen, Gerbren Jacobs, Marjo S. van der Knaap, Vivi M. HeineSummaryStem cell therapy has great prospects for brain white matter disorders, including the genetically determined disorders called leukodystrophies. We focus on the devastating leukodystrophy vanishing white matter (VWM). Patients with VWM show severe disability and early death, and treatment options are lacking. Previous studies showed successful cell replacement therapy in rod...
Source: Stem Cell Reports - Category: Stem Cells Source Type: research
Mucopolysaccharidosis type IH (MPS1/Hurler Syndrome), cerebral adrenoleukodystrophy (cALD), metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy (GLD) are fatal IMDs affecting the central nervous system treatable through allogeneic hematopoietic stem cell transplantation (HSCT). In the absence of a non-carrier HLA matched related donor, cord blood (CB) is the preferred source of cells in IMDs due to rapid availability and flexibility in matching. However, prolonged neutropenia and high graft failure rates present a challenge, particularly with reduced intensity conditioning regimens.
Source: Biology of Blood and Marrow Transplantation - Category: Hematology Authors: Tags: 122 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
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 operation of the nervous system, and as a consequence demyelinating conditions such as multiple sclerosis are unpleasant and fatal. Loss of myelin isn't just restricted to named conditions, however: some degree of degradation occurs over the course of aging, and is thought to contribute to the progression of cognitive decline. Thus therapies that can boost myelin maintenance may be of greater interest than it might at first appear. Myelin is mai...
Source: Fight Aging! - Category: Research Authors: Tags: Daily News Source Type: blogs
Background: IMDs including mucopolysaccharidosis type IH (MPS1/Hurler Syndrome), metachromatic leukodystrophy (MLD), globoid cell leukodystrophy (GLD) and cerebral adrenoleukodystrophy (cALD) are progressive, fatal diseases affecting the central nervous system which are treatable through allogeneic hematopoietic stem cell transplantation (HSCT). CB, in the absence of a matched donor, is the preferred source of stem cells as it is rapidly available and allows greater flexibility in allele matching. As a result of low cell doses, CB transplants in IMD are associated with prolonged periods of neutropenia and reported graft fa...
Source: Blood - Category: Hematology Authors: Tags: 732. Clinical Allogeneic Transplantation: Results: Poster II 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 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
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