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Ken Inoue - One of the best experts on this subject based on the ideXlab platform.

  • Pelizaeus-Merzbacher Disease: Molecular and Cellular Pathologies and Associated Phenotypes.
    Advances in experimental medicine and biology, 2019
    Co-Authors: Ken Inoue
    Abstract:

    Pelizaeus-Merzbacher Disease (PMD) represents a group of disorders known as hypomyelinating leukodystrophies, which are characterized by abnormal development and maintenance of myelin in the central nervous system. PMD is caused by different types of mutations in the proteolipid protein 1 (PLP1) gene, which encodes a major myelin membrane lipoprotein. These mutations in the PLP1 gene result in distinct cellular and molecular pathologies and a spectrum of clinical phenotypes. In this chapter, I discuss the historical aspects and current understanding of the mechanisms underlying how different PLP1 mutations disrupt the normal process of myelination and result in PMD and other disorders.

  • Gene suppressing therapy for Pelizaeus-Merzbacher Disease using artificial microRNA
    JCI insight, 2019
    Co-Authors: Heng Li, Hironori Okada, Sadafumi Suzuki, Kazuhisa Sakai, Hitomi Izumi, Yukiko Matsushima, Noritaka Ichinohe, Yu-ichi Goto, Takashi Okada, Ken Inoue
    Abstract:

    Copy number increase or decrease of certain dosage-sensitive genes may cause genetic Diseases with distinct phenotypes, conceptually termed genomic disorders. The most common cause of Pelizaeus-Merzbacher Disease (PMD), an X-linked hypomyelinating leukodystrophy, is genomic duplication encompassing the entire proteolipid protein 1 (PLP1) gene. Although the exact molecular and cellular mechanisms underlying PLP1 duplication, which causes severe hypomyelination in the central nervous system, remain largely elusive, PLP1 overexpression is likely the fundamental cause of this devastating Disease. Here, we investigated if adeno-associated virus–mediated (AAV-mediated) gene-specific suppression may serve as a potential cure for PMD by correcting quantitative aberrations in gene products. We developed an oligodendrocyte-specific Plp1 gene suppression therapy using artificial microRNA under the control of human CNP promoter in a self-complementary AAV (scAAV) platform. A single direct brain injection achieved widespread oligodendrocyte-specific Plp1 suppression in the white matter of WT mice. AAV treatment in Plp1-transgenic mice, a PLP1 duplication model, ameliorated cytoplasmic accumulation of Plp1, preserved mature oligodendrocytes from degradation, restored myelin structure and gene expression, and improved survival and neurological phenotypes. Together, our results provide evidence that AAV-mediated gene suppression therapy can serve as a potential cure for PMD resulting from PLP1 duplication and possibly for other genomic disorders.

  • cellular pathology of Pelizaeus Merzbacher Disease involving chaperones associated with endoplasmic reticulum stress
    Frontiers in Molecular Biosciences, 2017
    Co-Authors: Ken Inoue
    Abstract:

    Disease-causing mutations in genes encoding membrane proteins may lead to the production of aberrant polypeptides that accumulate in the endoplasmic reticulum (ER). These mutant proteins have detrimental conformational changes or misfolding events, which result in the triggering of the unfolded protein response (UPR). UPR is a cellular pathway that reduces ER stress by generally inhibiting translation, increasing ER chaperones levels, or inducing cell apoptosis in severe ER stress. This process has been implicated in the cellular pathology of many neurological disorders, including Pelizaeus-Merzbacher Disease (PMD). PMD is a rare pediatric disorder characterized by the failure in the myelination process of the central nervous system (CNS). PMD is caused by mutations in the PLP1 gene, which encodes a major myelin membrane protein. Severe clinical PMD phenotypes appear to be the result of cell toxicity, due to the accumulation of PLP1 mutant proteins and not due to the lack of functional PLP1. Therefore, it is important to clarify the pathological mechanisms by which the PLP1 mutants negatively impact the myelin-generating cells, called oligodendrocytes, to overcome this devastating Disease. This review discusses how PLP1 mutant proteins change protein homeostasis in the ER of oligodendrocytes, especially focusing on the reaction of ER chaperones against the accumulation of PLP1 mutant proteins that cause PMD.

  • a splicing mutation of proteolipid protein 1 in Pelizaeus Merzbacher Disease
    Brain & Development, 2016
    Co-Authors: Taku Omata, Shiro Koizume, Junichi Nagai, Hiroko Shimbo, Sumimasa Yamashita, Kenji Kurosawa, Hitoshi Osaka, Yohei Miyagi, Ken Inoue
    Abstract:

    A patient with an unusually mild form of Pelizaeus-Merzbacher Disease was studied. Clinically, mild developmental delay with acquisition of assisted walking at 16months and mild spastic tetraplegia were evident, but no nystagmus, cerebellar, or extra-pyramidal signs were present. PLP1 mutation analysis revealed a nucleotide substitution adjacent to the acceptor site of intron 3, NM_000533.4:c.454-9T>G. Expression analysis using the patient's leukocytes demonstrated an additional abnormal transcript including the last 118bp of intron 3. In silico prediction analysis suggested the reduction of wild-type acceptor activity, which presumably evokes the cryptic splicing variant. Putative cryptic transcript results in premature termination, which may explain the mild clinical phenotype observed in this patient.

  • case report a splicing mutation of proteolipid protein 1 in Pelizaeus Merzbacher Disease
    2016
    Co-Authors: Taku Omata, Shiro Koizume, Junichi Nagai, Hiroko Shimbo, Sumimasa Yamashita, Kenji Kurosawa, Hitoshi Osaka, Yohei Miyagi, Ken Inoue
    Abstract:

    A patient with an unusually mild form of Pelizaeus-Merzbacher Disease was studied. Clinically, mild developmental delay with acquisition of assisted walking at 16 months and mild spastic tetraplegia were evident, but no nystagmus, cerebellar, or extrapyramidal signs were present. PLP1 mutation analysis revealed a nucleotide substitution adjacent to the acceptor site of intron 3, NM_000533.4:c.454-9T>G. Expression analysis using the patient’s leukocytes demonstrated an additional abnormal transcript including the last 118 bp of intron 3. In silico prediction analysis suggested the reduction of wild-type acceptor activity, which presumably evokes the cryptic splicing variant. Putative cryptic transcript results in premature termination, which may explain the mild clinical phenotype observed in this patient.

Hitoshi Osaka - One of the best experts on this subject based on the ideXlab platform.

  • a splicing mutation of proteolipid protein 1 in Pelizaeus Merzbacher Disease
    Brain & Development, 2016
    Co-Authors: Taku Omata, Shiro Koizume, Junichi Nagai, Hiroko Shimbo, Sumimasa Yamashita, Kenji Kurosawa, Hitoshi Osaka, Yohei Miyagi, Ken Inoue
    Abstract:

    A patient with an unusually mild form of Pelizaeus-Merzbacher Disease was studied. Clinically, mild developmental delay with acquisition of assisted walking at 16months and mild spastic tetraplegia were evident, but no nystagmus, cerebellar, or extra-pyramidal signs were present. PLP1 mutation analysis revealed a nucleotide substitution adjacent to the acceptor site of intron 3, NM_000533.4:c.454-9T>G. Expression analysis using the patient's leukocytes demonstrated an additional abnormal transcript including the last 118bp of intron 3. In silico prediction analysis suggested the reduction of wild-type acceptor activity, which presumably evokes the cryptic splicing variant. Putative cryptic transcript results in premature termination, which may explain the mild clinical phenotype observed in this patient.

  • case report a splicing mutation of proteolipid protein 1 in Pelizaeus Merzbacher Disease
    2016
    Co-Authors: Taku Omata, Shiro Koizume, Junichi Nagai, Hiroko Shimbo, Sumimasa Yamashita, Kenji Kurosawa, Hitoshi Osaka, Yohei Miyagi, Ken Inoue
    Abstract:

    A patient with an unusually mild form of Pelizaeus-Merzbacher Disease was studied. Clinically, mild developmental delay with acquisition of assisted walking at 16 months and mild spastic tetraplegia were evident, but no nystagmus, cerebellar, or extrapyramidal signs were present. PLP1 mutation analysis revealed a nucleotide substitution adjacent to the acceptor site of intron 3, NM_000533.4:c.454-9T>G. Expression analysis using the patient’s leukocytes demonstrated an additional abnormal transcript including the last 118 bp of intron 3. In silico prediction analysis suggested the reduction of wild-type acceptor activity, which presumably evokes the cryptic splicing variant. Putative cryptic transcript results in premature termination, which may explain the mild clinical phenotype observed in this patient.

  • Involvement of ER Stress in Dysmyelination of Pelizaeus-Merzbacher Disease with PLP1 Missense Mutations Shown by iPSC-Derived Oligodendrocytes
    Stem cell reports, 2014
    Co-Authors: Yuko Numasawa-kuroiwa, Wado Akamatsu, Masanobu Shoji, Manabu Oyama, Shinsuke Shibata, Hitoshi Osaka, Noriyuki Kishi, Atsushi Nakanishi, Yohei Okada, Ken Inoue
    Abstract:

    Pelizaeus-Merzbacher Disease (PMD) is a form of X-linked leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene. Although PLP1 proteins with missense mutations have been shown to accumulate in the rough endoplasmic reticulum (ER) in Disease model animals and cell lines transfected with mutant PLP1 genes, the exact pathogenetic mechanism of PMD has not previously been clarified. In this study, we established induced pluripotent stem cells (iPSCs) from two PMD patients carrying missense mutation and differentiated them into oligodendrocytes in vitro. In the PMD iPSC-derived oligodendrocytes, mislocalization of mutant PLP1 proteins to the ER and an association between increased susceptibility to ER stress and increased numbers of apoptotic oligodendrocytes were observed. Moreover, electron microscopic analysis demonstrated drastically reduced myelin formation accompanied by abnormal ER morphology. Thus, this study demonstrates the involvement of ER stress in pathogenic dysmyelination in the oligodendrocytes of PMD patients with the PLP1 missense mutation.

  • effect of curcumin in a mouse model of Pelizaeus Merzbacher Disease
    Molecular Genetics and Metabolism, 2012
    Co-Authors: Toshifumi Morimura, Hitoshi Osaka, Yu-ichi Goto, Yurika Numata, Ryoko Yamamoto, Naoko Inoue, Barbara Antalfy, Kimiko Deguchi, Ken Inoue
    Abstract:

    PLP1 amino acid substitutions cause accumulation of misfolded protein and induce endoplasmic reticulum (ER) stress, causing Pelizaeus-Merzbacher Disease (PMD), a hypomyelinating disorder of the central nerve system. Currently no effective therapy is available for PMD. Promoted by its curative effects in other genetic Disease models caused by similar molecular mechanisms, we tested if curcumin, a dietary compound, can rescue the lethal phenotype of a PMD mouse model (myelin synthesis deficient, msd). Curcumin was administered orally to myelin synthesis deficit (msd) mice at 180 mg·kg(-1)·day(-1) from the postnatal day 3. We evaluated general and motor status, changes in myelination and apoptosis of oligodendrocytes by neuropathological and biochemical examination, and transcription levels for ER-related molecules. We also examined the pharmacological effect of curcumin in cell culture system. Oral curcumin treatment resulted in 25% longer survival (p<0.01). In addition, oligodendrocytes undergoing apoptosis were reduced in number (p<0.05). However, no apparent improvement in motor function, neurological phenotype, and myelin formation was observed. Curcumin treatment did not change the expression of ER stress markers and subcellular localization of the mutant protein in vitro and/or in vivo. Curcumin partially mitigated the clinical and pathological phenotype of msd mice, although molecular mechanisms underlying this curative effect are yet undetermined. Nonetheless, curcumin may serve as a potential therapeutic compound for PMD caused by PLP1 point mutations.

  • Mild phenotype in Pelizaeus-Merzbacher Disease caused by a PLP1-specific mutation
    Brain & Development, 2009
    Co-Authors: Hitoshi Osaka, Shiro Koizume, Junichi Nagai, Haruhiko Aoyama, Kenji Kurosawa, Hiroko Iwamoto, Seiji Kimura, Sumimasa Yamashita
    Abstract:

    Abstract We present the case of a 26 year-old man who developed normally until he began having difficulty walking at age 12. He subsequently became unable to stand at 15 years old and exhibited mental regression and generalized tonic convulsions by age 20. Magnetic resonance imaging revealed incomplete myelination of cerebral white matter, which resembled that of Pelizaeus-Merzbacher Disease. By sequencing the proteolipid protein 1 ( PLP1 ) gene, we found a novel mutation (c.352_353delAG (p.Gly130fs)) in the latter half of exon 3 (exon 3B) that is spliced out in the DM20 isoform. Exon 3B mutations are known to cause a mild phenotype since they do not disturb DM20 production. Mutations that truncate PLP1 correlate with a mild phenotype by activating the nonsense-mediated decay mechanism that specifically detects and degrades mRNAs containing a premature termination codon. This attenuates the production of toxic mutant PLP1. The very mild presentation in the present case seems to be derived from the unique nature of the mutation, which preserves DM20 production and decreases mutant PLP1.

Klausarmin Nave - One of the best experts on this subject based on the ideXlab platform.

  • curcumin therapy in a plp1 transgenic mouse model of Pelizaeus Merzbacher Disease
    Annals of clinical and translational neurology, 2015
    Co-Authors: Dirk B Epplen, Klausarmin Nave, Thomas Prukop, Tobias Nientiedt, Philipp Albrecht, Friederike A Arlt, Ruth M Stassart, Celia M Kassmann, Axel Methner, Hauke B Werner
    Abstract:

    Objective Pelizaeus–Merzbacher Disease (PMD) is a progressive and lethal leukodystrophy caused by mutations affecting the proteolipid protein (PLP1) gene. The most common cause of PMD is a duplication of PLP1 and at present there is no curative therapy available. Methods By using transgenic mice carrying additional copies of Plp1, we investigated whether curcumin diet ameliorates PMD symptoms. The diet of Plp1 transgenic mice was supplemented with curcumin for 10 consecutive weeks followed by phenotypical, histological and immunohistochemical analyses of the central nervous system. Plp1 transgenic and wild-type mice fed with normal chow served as controls. Results Curcumin improved the motor phenotype performance of Plp1 transgenic mice by 50% toward wild-type level and preserved myelinated axons by 35% when compared to Plp1 transgenic controls. Furthermore, curcumin reduced astrocytosis, microgliosis and lymphocyte infiltration in Plp1 transgenic mice. Curcumin diet did not affect the pathologically increased Plp1 mRNA abundance. However, high glutathione levels indicating an oxidative misbalance in the white matter of Plp1 transgenic mice were restored by curcumin treatment. Interpretation Curcumin may potentially serve as an antioxidant therapy of PMD caused by PLP1 gene duplication.

  • therapy of Pelizaeus Merzbacher Disease in mice by feeding a cholesterol enriched diet
    Nature Medicine, 2012
    Co-Authors: Gesine Saher, Wiebke Mobius, Fabian Rudolphi, Kristina Corthals, Torben Ruhwedel, Karlfriedrich Schmidt, Siegrid Lowel, Payam Dibaj, Benoit Barrette, Klausarmin Nave
    Abstract:

    Duplication of PLP1 (proteolipid protein gene 1) and the subsequent overexpression of the myelin protein PLP (also known as DM20) in oligodendrocytes is the most frequent cause of Pelizaeus-Merzbacher Disease (PMD), a fatal leukodystrophy without therapeutic options. PLP binds cholesterol and is contained within membrane lipid raft microdomains. Cholesterol availability is the rate-limiting factor of central nervous system myelin synthesis. Transgenic mice with extra copies of the Plp1 gene are accurate models of PMD. Dysmyelination followed by demyelination, secondary inflammation and axon damage contribute to the severe motor impairment in these mice. The finding that in Plp1-transgenic oligodendrocytes, PLP and cholesterol accumulate in late endosomes and lysosomes (endo/lysosomes), prompted us to further investigate the role of cholesterol in PMD. Here we show that cholesterol itself promotes normal PLP trafficking and that dietary cholesterol influences PMD pathology. In a preclinical trial, PMD mice were fed a cholesterol-enriched diet. This restored oligodendrocyte numbers and ameliorated intracellular PLP accumulation. Moreover, myelin content increased, inflammation and gliosis were reduced and motor defects improved. Even after onset of clinical symptoms, cholesterol treatment prevented Disease progression. Dietary cholesterol did not reduce Plp1 overexpression but facilitated incorporation of PLP into myelin membranes. These findings may have implications for therapeutic interventions in patients with PMD.

  • misalignment of plp dm20 transmembrane domains determines protein misfolding in Pelizaeus Merzbacher Disease
    The Journal of Neuroscience, 2011
    Co-Authors: Ajit Singh Dhaunchak, David R Colman, Klausarmin Nave
    Abstract:

    A large number of genetic Diseases have been associated with truncated or misfolded membrane proteins trapped in the endoplasmic reticulum (ER). In the ER, they activate the unfolded protein response, which can trigger cell death. Hence, a better understanding of protein misfolding features might help in developing novel therapies. Here, we have studied the molecular basis of Pelizaeus–Merzbacher Disease, a leukodystrophy defined by mutations of the PLP1 gene and ER retention of two encoded tetraspan myelin proteins, PLP and DM20. In mouse oligodendroglial cells, mutant isoforms of PLP/DM20 with fewer than all four transmembrane (TM) domains are fully ER retained. Surprisingly, a truncated PLP with only two N-terminal TM domains shows normal cell-surface expression when coexpressed with a second truncated PLP harboring the two C-terminal TM domains. This striking ability to properly self-align the TM domains is Disease relevant, as shown for the smaller splice isoform DM20. Here, the increased length of TM domain 3 allows for compensation of the effect of several PLP1 point mutations that impose a conformational constraint onto the adjacent extracellular loop region. We conclude that an important determinant in the quality control of polytopic membrane proteins is the free alignment of their TM domains.

  • demyelination and axonal preservation in a transgenic mouse model of Pelizaeus Merzbacher Disease
    Embo Molecular Medicine, 2010
    Co-Authors: Julia M Edgar, Mailis C Mcculloch, Paul Montague, Angus M Brown, Sebastian Thilemann, Laura Pratola, Fredrik I Gruenenfelder, I R Griffiths, Klausarmin Nave
    Abstract:

    It is widely thought that demyelination contributes to the degeneration of axons and, in combination with acute inflammatory injury, is responsible for progressive axonal loss and persistent clinical disability in inflammatory demyelinating Disease. In this study we sought to characterize the relationship between demyelination, inflammation and axonal transport changes using a Plp1-transgenic mouse model of Pelizaeus-Merzbacher Disease. In the optic pathway of this non-immune mediated model of demyelination, myelin loss progresses from the optic nerve head towards the brain, over a period of months. Axonal transport is functionally perturbed at sites associated with local inflammation and ‘damaged’ myelin. Surprisingly, where demyelination is complete, naked axons appear well preserved despite a significant reduction of axonal transport. Our results suggest that neuroinflammation and/or oligodendrocyte dysfunction are more deleterious for axonal health than demyelination per se, at least in the short term.

  • a common mechanism of plp dm20 misfolding causes cysteine mediated endoplasmic reticulum retention in oligodendrocytes and Pelizaeus Merzbacher Disease
    Proceedings of the National Academy of Sciences of the United States of America, 2007
    Co-Authors: Ajit Singh Dhaunchak, Klausarmin Nave
    Abstract:

    A large number of mutations in the human PLP1 gene lead to abnormal myelination and oligodendrocyte death in Pelizaeus–Merzbacher Disease (PMD). Here we show that a major subgroup of PMD mutations that map into the extracellular loop region of PLP/DM20 leads to the failure of oligodendrocytes to form the correct intramolecular disulfide bridges. This leads to abnormal protein cross-links and endoplasmic reticulum retention and activates the unfolded protein response. Importantly, surface expression of mutant PLP/DM20 can be restored and the unfolded protein response can be reverted by the removal of two cysteines. Thus, covalent protein cross-links emerge as a cause, rather than as a consequence, of endoplasmic reticulum retention.

Matthew S Elitt - One of the best experts on this subject based on the ideXlab platform.

  • Suppression of proteolipid protein rescues Pelizaeus-Merzbacher Disease
    Nature, 2020
    Co-Authors: Matthew S Elitt, Lilianne Barbar, H. Elizabeth Shick, Berit E. Powers, Yuka Maeno-hikichi, Baraa S. Nawash, Mayur Madhavan, Kevin C Allan, Artur S. Gevorgyan, Stevephen Hung
    Abstract:

    Mutations in PLP1, the gene that encodes proteolipid protein (PLP), result in failure of myelination and neurological dysfunction in the X-chromosome-linked leukodystrophy Pelizaeus–Merzbacher Disease (PMD)1,2. Most PLP1 mutations, including point mutations and supernumerary copy variants, lead to severe and fatal Disease. Patients who lack PLP1 expression, and Plp1-null mice, can display comparatively mild phenotypes, suggesting that PLP1 suppression might provide a general therapeutic strategy for PMD1,3–5. Here we show, using CRISPR–Cas9 to suppress Plp1 expression in the jimpy (Plp1jp) point-mutation mouse model of severe PMD, increased myelination and restored nerve conduction velocity, motor function and lifespan of the mice to wild-type levels. To evaluate the translational potential of this strategy, we identified antisense oligonucleotides that stably decrease the levels of Plp1 mRNA and PLP protein throughout the neuraxis in vivo. Administration of a single dose of Plp1-targeting antisense oligonucleotides in postnatal jimpy mice fully restored oligodendrocyte numbers, increased myelination, improved motor performance, normalized respiratory function and extended lifespan up to an eight-month end point. These results suggest that PLP1 suppression could be developed as a treatment for PMD in humans. More broadly, we demonstrate that oligonucleotide-based therapeutic agents can be delivered to oligodendrocytes in vivo to modulate neurological function and lifespan, establishing a new pharmaceutical modality for myelin disorders. In a mouse model of the leukodystrophy Pelizaeus–Merzbacher Disease, myelination, motor performance, respiratory function and lifespan are improved by suppressing proteolipid protein expression, suggesting PLP1 as a therapeutic target for human patients with this Disease and, more broadly, antisense oligonucleotides as a pharmaceutical modality for treatment of myelin disorders.

  • Therapeutic suppression of proteolipid protein rescues Pelizaeus-Merzbacher Disease in mice
    bioRxiv, 2018
    Co-Authors: Matthew S Elitt, Lilianne Barbar, H. Elizabeth Shick, Berit E. Powers, Yuka Maeno-hikichi, Baraa S. Nawash, Zachary S. Nevin, Mayur Madhavan, Kevin C Allan, Hannah E. Olsen
    Abstract:

    Mutations in proteolipid protein 1 (PLP1) result in failure of myelination and severe neurological dysfunction in the X-linked pediatric leukodystrophy Pelizaeus-Merzbacher Disease (PMD). The majority of PLP1 variants, including supernumerary copies and various point mutations, lead to early mortality. However, PLP1-null patients and mice display comparatively mild phenotypes, suggesting that reduction of aberrant PLP1 expression might provide a therapeutic strategy across PMD genotypes. Here we show, CRISPR-Cas9 mediated germline knockdown of Plp1 in the severe jimpy (Plp1jp) point mutation mouse model of PMD rescued myelinating oligodendrocytes, nerve conduction velocity, motor function, and lifespan to wild-type levels, thereby validating PLP1 suppression as a therapeutic approach. To evaluate the therapeutic potential of Plp1 suppression in postnatal PMD mice, we tested antisense oligonucleotides (ASOs) that stably decrease mouse Plp1 mRNA and protein in vivo. Administration of a single intraventricular dose of Plp1-targeted ASOs to postnatal jimpy mice increased myelination, improved motor behavior, and extended lifespan through an 8-month endpoint. Collectively, these results support the development of PLP1 suppression as a Disease-modifying therapy for most PMD patients. More broadly, we demonstrate that RNA therapeutics can be delivered to oligodendrocytes in vivo to modulate neurological function and lifespan, opening a new treatment modality for myelin disorders.

  • chemical screening identifies enhancers of mutant oligodendrocyte survival and unmasks a distinct pathological phase in Pelizaeus Merzbacher Disease
    Stem cell reports, 2018
    Co-Authors: Matthew S Elitt, Lilianne Barbar, Mayur Madhavan, Kevin C Allan, Elizabeth H. Shick, Benjamin L.l. Clayton, Chen Weng, Tyler E. Miller, Daniel C. Factor, Baraa S. Nawash
    Abstract:

    Summary Pelizaeus-Merzbacher Disease (PMD) is a fatal X-linked disorder caused by loss of myelinating oligodendrocytes and consequent hypomyelination. The underlying cellular and molecular dysfunctions are not fully defined, but therapeutic enhancement of oligodendrocyte survival could restore functional myelination in patients. Here we generated pure, scalable quantities of induced pluripotent stem cell-derived oligodendrocyte progenitor cells (OPCs) from a severe mouse model of PMD, Plp1 jimpy . Temporal phenotypic and transcriptomic studies defined an early pathological window characterized by endoplasmic reticulum (ER) stress and cell death as OPCs exit their progenitor state. High-throughput phenotypic screening identified a compound, Ro 25–6981, which modulates the ER stress response and rescues mutant oligodendrocyte survival in jimpy , in vitro and in vivo , and in human PMD oligocortical spheroids. Surprisingly, increasing oligodendrocyte survival did not restore subsequent myelination, revealing a second pathological phase. Collectively, our work shows that PMD oligodendrocyte loss can be rescued pharmacologically and defines a need for multifactorial intervention to restore myelination.

  • Chemical Screening Identifies Enhancers of Mutant Oligodendrocyte Survival and Unmasks a Distinct Pathological Phase in Pelizaeus-Merzbacher Disease
    'Elsevier BV', 2018
    Co-Authors: Matthew S Elitt, Lilianne Barbar, Mayur Madhavan, Kevin C Allan, Elizabeth H. Shick, Benjamin L.l. Clayton, Chen Weng, Tyler E. Miller, Daniel C. Factor, Baraa S. Nawash
    Abstract:

    Summary: Pelizaeus-Merzbacher Disease (PMD) is a fatal X-linked disorder caused by loss of myelinating oligodendrocytes and consequent hypomyelination. The underlying cellular and molecular dysfunctions are not fully defined, but therapeutic enhancement of oligodendrocyte survival could restore functional myelination in patients. Here we generated pure, scalable quantities of induced pluripotent stem cell-derived oligodendrocyte progenitor cells (OPCs) from a severe mouse model of PMD, Plp1jimpy. Temporal phenotypic and transcriptomic studies defined an early pathological window characterized by endoplasmic reticulum (ER) stress and cell death as OPCs exit their progenitor state. High-throughput phenotypic screening identified a compound, Ro 25–6981, which modulates the ER stress response and rescues mutant oligodendrocyte survival in jimpy, in vitro and in vivo, and in human PMD oligocortical spheroids. Surprisingly, increasing oligodendrocyte survival did not restore subsequent myelination, revealing a second pathological phase. Collectively, our work shows that PMD oligodendrocyte loss can be rescued pharmacologically and defines a need for multifactorial intervention to restore myelination. : Tesar and colleagues interrogate the severe genetic myelin disorder Pelizaeus-Merzbacher Disease (PMD) using iPSC-derived oligodendrocyte progenitor cells (OPCs). Using high-throughput phenotypic screening, they rescue cell death of mutant oligodendrocytes immediately after initiation of differentiation with chemical modulators, including Ro 25–6981. Interestingly oligodendrocyte restoration did not lead to widespread myelination, unmasking a new phase of the Disease. Keywords: iPSC Disease modeling, high-throughput screening, oligodendrocyte progenitor cells, oligodendrocytes, myelin, Pelizaeus-Merzbacher Disease, proteolipid protein 1, endoplasmic reticulum stress, PLP1, rare diseas

Baraa S. Nawash - One of the best experts on this subject based on the ideXlab platform.

  • Suppression of proteolipid protein rescues Pelizaeus-Merzbacher Disease
    Nature, 2020
    Co-Authors: Matthew S Elitt, Lilianne Barbar, H. Elizabeth Shick, Berit E. Powers, Yuka Maeno-hikichi, Baraa S. Nawash, Mayur Madhavan, Kevin C Allan, Artur S. Gevorgyan, Stevephen Hung
    Abstract:

    Mutations in PLP1, the gene that encodes proteolipid protein (PLP), result in failure of myelination and neurological dysfunction in the X-chromosome-linked leukodystrophy Pelizaeus–Merzbacher Disease (PMD)1,2. Most PLP1 mutations, including point mutations and supernumerary copy variants, lead to severe and fatal Disease. Patients who lack PLP1 expression, and Plp1-null mice, can display comparatively mild phenotypes, suggesting that PLP1 suppression might provide a general therapeutic strategy for PMD1,3–5. Here we show, using CRISPR–Cas9 to suppress Plp1 expression in the jimpy (Plp1jp) point-mutation mouse model of severe PMD, increased myelination and restored nerve conduction velocity, motor function and lifespan of the mice to wild-type levels. To evaluate the translational potential of this strategy, we identified antisense oligonucleotides that stably decrease the levels of Plp1 mRNA and PLP protein throughout the neuraxis in vivo. Administration of a single dose of Plp1-targeting antisense oligonucleotides in postnatal jimpy mice fully restored oligodendrocyte numbers, increased myelination, improved motor performance, normalized respiratory function and extended lifespan up to an eight-month end point. These results suggest that PLP1 suppression could be developed as a treatment for PMD in humans. More broadly, we demonstrate that oligonucleotide-based therapeutic agents can be delivered to oligodendrocytes in vivo to modulate neurological function and lifespan, establishing a new pharmaceutical modality for myelin disorders. In a mouse model of the leukodystrophy Pelizaeus–Merzbacher Disease, myelination, motor performance, respiratory function and lifespan are improved by suppressing proteolipid protein expression, suggesting PLP1 as a therapeutic target for human patients with this Disease and, more broadly, antisense oligonucleotides as a pharmaceutical modality for treatment of myelin disorders.

  • Therapeutic suppression of proteolipid protein rescues Pelizaeus-Merzbacher Disease in mice
    bioRxiv, 2018
    Co-Authors: Matthew S Elitt, Lilianne Barbar, H. Elizabeth Shick, Berit E. Powers, Yuka Maeno-hikichi, Baraa S. Nawash, Zachary S. Nevin, Mayur Madhavan, Kevin C Allan, Hannah E. Olsen
    Abstract:

    Mutations in proteolipid protein 1 (PLP1) result in failure of myelination and severe neurological dysfunction in the X-linked pediatric leukodystrophy Pelizaeus-Merzbacher Disease (PMD). The majority of PLP1 variants, including supernumerary copies and various point mutations, lead to early mortality. However, PLP1-null patients and mice display comparatively mild phenotypes, suggesting that reduction of aberrant PLP1 expression might provide a therapeutic strategy across PMD genotypes. Here we show, CRISPR-Cas9 mediated germline knockdown of Plp1 in the severe jimpy (Plp1jp) point mutation mouse model of PMD rescued myelinating oligodendrocytes, nerve conduction velocity, motor function, and lifespan to wild-type levels, thereby validating PLP1 suppression as a therapeutic approach. To evaluate the therapeutic potential of Plp1 suppression in postnatal PMD mice, we tested antisense oligonucleotides (ASOs) that stably decrease mouse Plp1 mRNA and protein in vivo. Administration of a single intraventricular dose of Plp1-targeted ASOs to postnatal jimpy mice increased myelination, improved motor behavior, and extended lifespan through an 8-month endpoint. Collectively, these results support the development of PLP1 suppression as a Disease-modifying therapy for most PMD patients. More broadly, we demonstrate that RNA therapeutics can be delivered to oligodendrocytes in vivo to modulate neurological function and lifespan, opening a new treatment modality for myelin disorders.

  • chemical screening identifies enhancers of mutant oligodendrocyte survival and unmasks a distinct pathological phase in Pelizaeus Merzbacher Disease
    Stem cell reports, 2018
    Co-Authors: Matthew S Elitt, Lilianne Barbar, Mayur Madhavan, Kevin C Allan, Elizabeth H. Shick, Benjamin L.l. Clayton, Chen Weng, Tyler E. Miller, Daniel C. Factor, Baraa S. Nawash
    Abstract:

    Summary Pelizaeus-Merzbacher Disease (PMD) is a fatal X-linked disorder caused by loss of myelinating oligodendrocytes and consequent hypomyelination. The underlying cellular and molecular dysfunctions are not fully defined, but therapeutic enhancement of oligodendrocyte survival could restore functional myelination in patients. Here we generated pure, scalable quantities of induced pluripotent stem cell-derived oligodendrocyte progenitor cells (OPCs) from a severe mouse model of PMD, Plp1 jimpy . Temporal phenotypic and transcriptomic studies defined an early pathological window characterized by endoplasmic reticulum (ER) stress and cell death as OPCs exit their progenitor state. High-throughput phenotypic screening identified a compound, Ro 25–6981, which modulates the ER stress response and rescues mutant oligodendrocyte survival in jimpy , in vitro and in vivo , and in human PMD oligocortical spheroids. Surprisingly, increasing oligodendrocyte survival did not restore subsequent myelination, revealing a second pathological phase. Collectively, our work shows that PMD oligodendrocyte loss can be rescued pharmacologically and defines a need for multifactorial intervention to restore myelination.

  • Chemical Screening Identifies Enhancers of Mutant Oligodendrocyte Survival and Unmasks a Distinct Pathological Phase in Pelizaeus-Merzbacher Disease
    'Elsevier BV', 2018
    Co-Authors: Matthew S Elitt, Lilianne Barbar, Mayur Madhavan, Kevin C Allan, Elizabeth H. Shick, Benjamin L.l. Clayton, Chen Weng, Tyler E. Miller, Daniel C. Factor, Baraa S. Nawash
    Abstract:

    Summary: Pelizaeus-Merzbacher Disease (PMD) is a fatal X-linked disorder caused by loss of myelinating oligodendrocytes and consequent hypomyelination. The underlying cellular and molecular dysfunctions are not fully defined, but therapeutic enhancement of oligodendrocyte survival could restore functional myelination in patients. Here we generated pure, scalable quantities of induced pluripotent stem cell-derived oligodendrocyte progenitor cells (OPCs) from a severe mouse model of PMD, Plp1jimpy. Temporal phenotypic and transcriptomic studies defined an early pathological window characterized by endoplasmic reticulum (ER) stress and cell death as OPCs exit their progenitor state. High-throughput phenotypic screening identified a compound, Ro 25–6981, which modulates the ER stress response and rescues mutant oligodendrocyte survival in jimpy, in vitro and in vivo, and in human PMD oligocortical spheroids. Surprisingly, increasing oligodendrocyte survival did not restore subsequent myelination, revealing a second pathological phase. Collectively, our work shows that PMD oligodendrocyte loss can be rescued pharmacologically and defines a need for multifactorial intervention to restore myelination. : Tesar and colleagues interrogate the severe genetic myelin disorder Pelizaeus-Merzbacher Disease (PMD) using iPSC-derived oligodendrocyte progenitor cells (OPCs). Using high-throughput phenotypic screening, they rescue cell death of mutant oligodendrocytes immediately after initiation of differentiation with chemical modulators, including Ro 25–6981. Interestingly oligodendrocyte restoration did not lead to widespread myelination, unmasking a new phase of the Disease. Keywords: iPSC Disease modeling, high-throughput screening, oligodendrocyte progenitor cells, oligodendrocytes, myelin, Pelizaeus-Merzbacher Disease, proteolipid protein 1, endoplasmic reticulum stress, PLP1, rare diseas