Peroxisomes in brain development and function

In the paper

“In the deep white matter, catalase-positive glia appeared at 31–32 weeks of gestation, their appearance shifting from the deep to the superficial white matter with increasing age [15].”

What the sources say

• Not checked yetcites [15] Houdou S Kuruta H Hasegawa M Konomi H Takashima S Suzuki Y Hashimoto T Developmental immunohistochemistry of catalase in the human brain Brain Res 1991 556 267 270 1933360

In the paper

“Moreover, the abundance of brain peroxisomes differs between brain areas. Although single membrane-bound structures – detectable with different methods to stain peroxisomes – can be found in most regions, some brain areas were reported to contain only modest numbers of peroxisomes [22].”

What the sources say

• Not checked yetcites [22] Arnold G Holtzman E Microperoxisomes in the central nervous system of the postnatal rat Brain Res 1978 155 1 17 688002

In the paper

“In contrast, the mRNAs for the enzymes involved in α-oxidation were not detected during the first postnatal weeks; and the ABCD1 mRNA was most highly expressed in the embryonic brain [26–28].”

What the sources say

• Not checked yetcites [26] Knoll A Sargueil F Salles J Cassagne C Garbay B Gene expression of peroxisomal beta-oxidation enzymes in rat brain Brain Res Mol Brain Res 1999 74 217 220 10640693
• Not checked yetcites [27] Huyghe S Casteels M Janssen A Meulders L Mannaerts GP Declercq PE Van Veldhoven PP Baes M Prenatal and postnatal development of peroxisomal lipid-metabolizing pathways in the mouse Biochem J 2001 353 673 680 11171065 PMC1221614
• Not checked yetcites [28] Berger J Albet S Bentejac M Netik A Holzinger A Roscher AA Bugaut M Forss-Petter S The four murine peroxisomal ABC-transporter genes differ in constitutive, inducible and developmental expression Eur J Biochem 1999 265 719 727 10504404 source

In the paper

“In the cerebellum, punctate catalase immunoreactivity (characteristic of a peroxisomal localization) was predominantly observed in Bergmann glia (astrocytes), whereas in Purkinje cells, catalase appeared evenly distributed.”

What the sources say

• Not checked yetcites [21] Nagase T Shimozawa N Takemoto Y Suzuki Y Komori M Kondo N Peroxisomal localization in the developing mouse cerebellum: implications for neuronal abnormalities related to deficiencies in peroxisomes Biochim Biophys Acta 2004 1671 26 33 15026142

In the paper

“In the human brain, catalase-positive neurons emerged early in evolutionary old structures such as the basal ganglia, the thalamus and the cerebellum (about 27–28 weeks of gestation), whereas in the frontal cortex, they appeared later (around 35 weeks of gestation) [15].”

What the sources say

• Not checked yetcites [15] Houdou S Kuruta H Hasegawa M Konomi H Takashima S Suzuki Y Hashimoto T Developmental immunohistochemistry of catalase in the human brain Brain Res 1991 556 267 270 1933360

In the paper

“Brain peroxisomes in general, and neuronal peroxisomes in particular, are smaller than peroxisomes from other tissues and, thus, were termed microperoxisomes [17].”

What the sources say

• Not checked yetcites [17] Holtzman E Teichberg S Abrahams SJ Citkowitz E Crain SM Kawai N Peterson ER Notes on synaptic vesicles and related structures, endoplasmic reticulum, lysosomes and peroxisomes in nervous tissue and the adrenal medulla J Histochem Cytochem 1973 21 349 385 4574997

In the paper

“In mammals, peroxisomes contain around 50 different proteins [2]”

What the sources say

• Not checked yetcites [2] Wiese S Gronemeyer T Ofman R Kunze M Grou CP Almeida JA Eisenacher M Stephan C Hayen H Schollenberger L Korosec T Proteomics characterization of mouse kidney peroxisomes by tandem mass spectrometry and protein correlation profiling Mol Cell Proteomics 2007 6 2045 2057 17768142

In the paper

“Comparison of DAO and catalase activity revealed that in the locus coeruleus of the rat brain, peroxisomes that stained positive for catalase activity were found in various cell types, whereas DAO activity-positive peroxisomes were restricted to astrocytes [13].”

What the sources say

• Not checked yetcites [13] Arnold G Liscum L Holtzman E Ultrastructural localization of D-amino acid oxidase in microperoxisomes of the rat nervous system J Histochem Cytochem 1979 27 735 745 39097

In the paper

“This fatty acid is enriched in phospholipids including ether phospholipids and, either directly or after enzymatic conversion to a variety of bioactive derivatives, plays an important role in signaling [12].”

What the sources say

• Not checked yetcites [12] Bazinet RP Laye S Polyunsaturated fatty acids and their metabolites in brain function and disease Nat Rev Neurosci 2014 15 771 785 25387473

In the paper

“This finding was recapitulated in explanted cells from the cerebellum, in which catalase appeared cytosolic (not enriched in peroxisomes) in calbindin-positive Purkinje cells but punctate in astrocytes, whereas the peroxisomal membrane protein PEX14 was found punctate in all cell types [21].”

What the sources say

• Not checked yetcites [21] Nagase T Shimozawa N Takemoto Y Suzuki Y Komori M Kondo N Peroxisomal localization in the developing mouse cerebellum: implications for neuronal abnormalities related to deficiencies in peroxisomes Biochim Biophys Acta 2004 1671 26 33 15026142

In the paper

“By now, mutations in 13 different peroxin (PEX) genes (PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX11b, PEX12, PEX13, PEX14, PEX16, PEX19, PEX26) have been described in patients of the Zellweger spectrum [45].”

What the sources say

• Not checked yetcites [45] Steinberg SJ Dodt G Raymond GV Braverman NE Moser AB Moser HW Peroxisome biogenesis disorders Biochim Biophys Acta 2006 1763 1733 1748 17055079

In the paper

“Peroxisomes are known to house a variety of oxidases generating H2O2 and ROS, but they also enclose various ROS-detoxifying enzymes such as catalase, GSTK1, PRDX5 and SOD1 to limit the detrimental effects of local production [8].”

What the sources say

• Not checked yetcites [8] Fransen M Nordgren M Wang B Apanasets O Role of peroxisomes in ROS/RNS-metabolism: implications for human disease Biochim Biophys Acta 2012 1822 1363 1373 22178243 source

In the paper

“To date, no migration defects have been described in infantile Refsum disease, the least severe form of the Zellweger spectrum.”

In the paper

“However, these patients have different clinical symptoms than Zellweger spectrum patients and are clinically not distinguishable from patients suffering from isolated disorders of ether phospholipid synthesis”

In the paper

“and exogenous application of VLCFA to a neuronal cell line induces oxidative stress and mitochondrial damage [35]”

What the sources say

• Not checked yetcites [35] Zarrouk A Vejux A Nury T El Hajj HI Haddad M Cherkaoui-Malki M Riedinger JM Hammami M Lizard G Induction of mitochondrial changes associated with oxidative stress on very long chain fatty acids (C22:0, C24:0, or C26:0)-treated human neuronal cells (SK-NB-E) Oxidative Med Cell Longev 2012 2012 623257 PMC3420217 22919440

In the paper

“Artificial local production of ROS inside peroxisomes can induce apoptosis, which can be rescued by ectopic overexpression of peroxisomal detoxifying enzymes [33].”

What the sources say

• Not checked yetcites [33] Wang B Van Veldhoven PP Brees C Rubio N Nordgren M Apanasets O Kunze M Baes M Agostinis P Fransen M Mitochondria are targets for peroxisome-derived oxidative stress in cultured mammalian cells Free Radic Biol Med 2013 65 882 894 23988789

In the paper

“The PBD are divided into two types, i) Zellweger spectrum disorders and ii) rhizomelic chondrodysplasia punctata (RCDP) type 1.”

In the paper

“In our current understanding, the clinical syndromes constituting the Zellweger spectrum (MIM #601539)2 are the Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease, which describe a clinical spectrum of decreasing severity [45].”

What the sources say

• Not checked yetcites [45] Steinberg SJ Dodt G Raymond GV Braverman NE Moser AB Moser HW Peroxisome biogenesis disorders Biochim Biophys Acta 2006 1763 1733 1748 17055079

In the paper

“In the polymicrogyric cortex, typically a fusion of the molecular layers is associated with a modified distribution of medium to large pyramidal cells originating from the deep cortex. This causes a decrease in the numbers of neurons in the outer layers (layer II and layer III) of the cortex; instead, these neurons are located in the deep cortex and within heterotopias of subcortical white matter”

What the sources say

• Not checked yetcites [6] Powers JM Moser HW Peroxisomal disorders: genotype, phenotype, major neuropathologic lesions, and pathogenesis Brain Pathol 1998 8 101 120 9458170 PMC8098283 source

In the paper

“Another striking morphological aberration linked to neuronal migration defects is the heterotopic localization of Purkinje cells in the cerebellar white matter (Fig. 2B) [6,49,50].”

What the sources say

• Not checked yetcites [6] Powers JM Moser HW Peroxisomal disorders: genotype, phenotype, major neuropathologic lesions, and pathogenesis Brain Pathol 1998 8 101 120 9458170 PMC8098283 source
• Not checked yetcites [49] Volpe JJ Adams RD Cerebro-hepato-renal syndrome of Zellweger: an inherited disorder of neuronal migration Acta Neuropathol 1972 20 175 198 5043999
• Not checked yetcites [50] Evrard P Caviness VS Jr Prats-Vinas J Lyon G The mechanism of arrest of neuronal migration in the Zellweger malformation: an hypothesis bases upon cytoarchitectonic analysis Acta Neuropathol 1978 41 109 117 636841

In the paper

“Patients with mutations in PEX7 are grouped into PBD because more than one peroxisomal pathway is affected, although the peroxisomal structure remains intact.”

In the paper

“Other studies reported normal VLCFA levels in plasma of late-onset patients with a PEX2 mutation [59] or normal plasmalogen levels in plasma of patients with PEX16 mutations [58].”

What the sources say

• Not checked yetcites [59] Sevin C Ferdinandusse S Waterham HR Wanders RJ Aubourg P Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene, Orphanet J Rare Dis 2011 6 8 PMC3064617 21392394
• Not checked yetcites [58] Ebberink MS Csanyi B Chong WK Denis S Sharp P Mooijer PA Dekker CJ Spooner C Ngu LH De Sousa C Wanders RJ Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene J Med Genet 2010 47 608 615 20647552

In the paper

“In particular, the levels of intermediates of bile acid biosynthesis (DHCA, THCA) and of pipecolic acid declined during the observed time period in many patients, whereas VLCFA and plasmalogen levels normalized only in some.”

What the sources say

• Not checked yetcites [47] Berendse K Engelen M Ferdinandusse S Majoie CB Waterham HR Vaz FM Koelman JH Barth PG Wanders RJ Poll-The BT Zellweger spectrum disorders: clinical manifestations in patients surviving into adulthood J Inherit Metab Dis 2015 PMC4710674 26287655

In the paper

“The number of granule cells was reduced due to defects in their migration from the external to the internal granule cell layer and increased apoptotic cell death.”

What the sources say

• Not checked yetcites [68] Faust PL Abnormal cerebellar histogenesis in PEX2 Zellweger mice reflects multiple neuronal defects induced by peroxisome deficiency J Comp Neurol 2003 461 394 413 12746876
• Not checked yetcites [69] Faust PL Banka D Siriratsivawong R Ng VG Wikander TM Peroxisome biogenesis disorders: the role of peroxisomes and metabolic dysfunction in developing brain J Inherit Metab Dis 2005 28 369 383 15868469

In the paper

“In all mice with a global peroxisome deficiency (Pex2, Pex5 and Pex13 deficiency), a reduced thickness of the neocortical plate was observed, which reflects abnormal lamination that has been linked to impaired neuronal migration and increased cellular density in the underlying white matter [60–62].”

What the sources say

• Not checked yetcites [60] Baes M Gressens P Baumgart E Carmeliet P Casteels M Fransen M Evrard P Fahimi D Declercq PE Collen D van Veldhoven PP A mouse model for Zellweger syndrome Nat Genet 1997 17 49 57 9288097
• Not checked yetcites [61] Faust PL Hatten ME Targeted deletion of the PEX2 peroxisome assembly gene in mice provides a model for Zellweger syndrome, a human neuronal migration disorder J Cell Biol 1997 139 1293 1305 9382874 PMC2140200
• Not checked yetcites [62] Maxwell M Bjorkman J Nguyen T Sharp P Finnie J Paterson C Tonks I Paton BC Kay GF Crane DI Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads to a Zellweger syndrome phenotype Mol Cell Biol 2003 23 5947 5957 12897163 PMC166343

In the paper

“When using mice, which express Cre under the nestin promoter (Nestin-Cre driver mice), inactivation of Pex5 occurs in all neural precursor cells at embryonic stages, but not in the microglia lineage.”

What the sources say

• Not checked yetcites [71] Hulshagen L Krysko O Bottelbergs A Huyghe S Klein R Van Veldhoven PP De Deyn PP D’Hooge R Hartmann D Baes M Absence of functional peroxisomes from mouse CNS causes dysmyelination and axon degeneration J Neurosci 2008 28 4015 4027 18400901 PMC6670456

In the paper

“During childhood, all 19 patients had a moderate to severe developmental delay as well as a reduction/loss of visual and hearing abilities and seven did not achieve structured speech.”

What the sources say

• Not checked yetcites [47] Berendse K Engelen M Ferdinandusse S Majoie CB Waterham HR Vaz FM Koelman JH Barth PG Wanders RJ Poll-The BT Zellweger spectrum disorders: clinical manifestations in patients surviving into adulthood J Inherit Metab Dis 2015 PMC4710674 26287655

In the paper

“As the import of peroxisomal proteins is not impaired in this mouse model, no accumulation of VLCFA and only a slight decrease in plasmalogen levels were detected in the brain [65].”

What the sources say

• Not checked yetcites [65] Li X Baumgart E Morrell JC Jimenez-Sanchez G Valle D Gould SJ PEX11 beta deficiency is lethal and impairs neuronal migration but does not abrogate peroxisome function Mol Cell Biol 2002 22 4358 4365 12024045 PMC133847

In the paper

“During infancy, four of these patients suffered from hypotonia, five from failure to thrive, 12 had a visual handicap due to retinal degeneration and eight presented with hearing impairment.”

What the sources say

• Not checked yetcites [47] Berendse K Engelen M Ferdinandusse S Majoie CB Waterham HR Vaz FM Koelman JH Barth PG Wanders RJ Poll-The BT Zellweger spectrum disorders: clinical manifestations in patients surviving into adulthood J Inherit Metab Dis 2015 PMC4710674 26287655

In the paper

“Interestingly, at the time of diagnosis, 17 of these patients had a blood metabolite profile typical of a peroxisomal disorder; but at later time points the concentration of many originally accumulating metabolites had declined and, in some patients, even a complete normalization was observed.”

What the sources say

• Not checked yetcites [47] Berendse K Engelen M Ferdinandusse S Majoie CB Waterham HR Vaz FM Koelman JH Barth PG Wanders RJ Poll-The BT Zellweger spectrum disorders: clinical manifestations in patients surviving into adulthood J Inherit Metab Dis 2015 PMC4710674 26287655

In the paper

“As Pex7-deficient mice represent a model for RCDP type 1, but not for Zellweger spectrum disorders, we discuss this model in the context of ether phospholipid deficiency (Section 5.5.).”

In the paper

“The phenotype of mice with Pex2, Pex5 and Pex13 deficiency resembles the severe form of human Zellweger syndrome. These mice are born alive, but are growth-retarded and severely hypotonic. Moreover, they do not feed and die within 67#x2013;24 h after birth [60–62].”

What the sources say

• Not checked yetcites [60] Baes M Gressens P Baumgart E Carmeliet P Casteels M Fransen M Evrard P Fahimi D Declercq PE Collen D van Veldhoven PP A mouse model for Zellweger syndrome Nat Genet 1997 17 49 57 9288097
• Not checked yetcites [61] Faust PL Hatten ME Targeted deletion of the PEX2 peroxisome assembly gene in mice provides a model for Zellweger syndrome, a human neuronal migration disorder J Cell Biol 1997 139 1293 1305 9382874 PMC2140200
• Not checked yetcites [62] Maxwell M Bjorkman J Nguyen T Sharp P Finnie J Paterson C Tonks I Paton BC Kay GF Crane DI Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads to a Zellweger syndrome phenotype Mol Cell Biol 2003 23 5947 5957 12897163 PMC166343

In the paper

“Moreover, mouse models with Pex11α [64] and Pex11β [65] deficiencies have been generated.”

What the sources say

• Not checked yetcites [64] Li X Baumgart E Dong GX Morrell JC Jimenez-Sanchez G Valle D Smith KD Gould SJ PEX11alpha is required for peroxisome proliferation in response to 4-phenylbutyrate but is dispensable for peroxisome proliferator-activated receptor alpha-mediated peroxisome proliferation Mol Cell Biol 2002 22 8226 8240 12417726 PMC134051
• Not checked yetcites [65] Li X Baumgart E Morrell JC Jimenez-Sanchez G Valle D Gould SJ PEX11 beta deficiency is lethal and impairs neuronal migration but does not abrogate peroxisome function Mol Cell Biol 2002 22 4358 4365 12024045 PMC133847

In the paper

“In these mice, peroxisome-dependent metabolite levels were deranged (increased VLCFA, decreased plasmalogen levels) in the brain at late embryonic stages, but were normal in the liver.”

What the sources say

• Not checked yetcites [71] Hulshagen L Krysko O Bottelbergs A Huyghe S Klein R Van Veldhoven PP De Deyn PP D’Hooge R Hartmann D Baes M Absence of functional peroxisomes from mouse CNS causes dysmyelination and axon degeneration J Neurosci 2008 28 4015 4027 18400901 PMC6670456

In the paper

“In Acox1−/− mice, marked peroxisome proliferation in the liver was observed and accompanied by an increase in H2O2 concentration, leading to the development of hepatic adenomas and carcinomas at 15 months of age [36]. However, no brain pathology has been described for these mice.”

What the sources say

• Not checked yetcites [36] Fan CY Pan J Usuda N Yeldandi AV Rao MS Reddy JK Steatohepatitis, spontaneous peroxisome proliferation and liver tumors in mice lacking peroxisomal fatty acyl-CoA oxidase. Implications for peroxisome proliferator-activated receptor alpha natural ligand metabolism J Biol Chem 1998 273 15639 15645 9624157 source

In the paper

“However, as both enzymatic steps are essential for peroxisomal β-oxidation, the complete loss of both activities as well as of the individual enzymatic activities causes neurodevelopmental abnormalities and death within the first two years of life [83].”

What the sources say

• Not checked yetcites [83] Ferdinandusse S Denis S Mooyer PA Dekker C Duran M Soorani-Lunsing RJ Boltshauser E Macaya A Gartner J Majoie CB Barth PG Clinical and biochemical spectrum of D-bifunctional protein deficiency Ann Neurol 2006 59 92 104 16278854

In the paper

“Peroxisomal β-oxidation can degrade VLCFA, branched-chain fatty acids, bile acid intermediates, long-chain dicarboxylic acids and polyunsaturated fatty acids like tetracosahexaenoic acid (C24:6), which undergoes one cycle of β-oxidation in peroxisomes to produce DHA (C22:6).”

In the paper

“Interestingly, no developmental defects were observed at birth or after two months although CNPase is expressed in progenitors before myelination as well as in adult oligodendrocytes.”

What the sources say

• Not checked yetcites [75] Kassmann CM Lappe-Siefke C Baes M Brugger B Mildner A Werner HB Natt O Michaelis T Prinz M Frahm J Nave KA Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes Nat Genet 2007 39 969 976 17643102

In the paper

“Human peroxisomes harbor two acyl-CoA oxidases, two bifunctional enzymes and two thiolases, whereas murine peroxisomes are equipped with three acyl-CoA oxidases, two bifunctional enzymes and three thiolases.”

In the paper

“The phenotype of patients with AMACR deficiency (MIM #614307) often involves adult-onset sensory neuropathy [94] and late-onset cerebellar ataxia [95].”

What the sources say

• Not checked yetcites [94] Smith EH Gavrilov DK Oglesbee D Freeman WD Vavra MW Matern D Tortorelli S An adult onset case of alpha-methyl-acyl-CoA racemase deficiency J Inherit Metab Dis 2010 33 Suppl. 3 S349 S353 20821052
• Not checked yetcites [95] Dick D Horvath R Chinnery PF AMACR mutations cause late-onset autosomal recessive cerebellar ataxia Neurology 2011 76 1768 1770 21576695 PMC3100132

In the paper

“Also brain-specific (Nestin-Cre-dependent) inactivation of Pex13 in mice resulted in a similar phenotype with impaired cerebellar development, neuronal cell death, astrogliosis and microgliosis as well as signs of mitochondria-mediated oxidative stress [74].”

What the sources say

• Not checked yetcites [74] Muller CC Nguyen TH Ahlemeyer B Meshram M Santrampurwala N Cao S Sharp P Fietz PB Baumgart-Vogt E Crane DI PEX13 deficiency in mouse brain as a model of Zellweger syndrome: abnormal cerebellum formation, reactive gliosis and oxidative stress Dis Model Mech 2011 4 104 119 20959636 PMC3014351

In the paper

“Moreover, Mfp2-deficient mice do not show signs of neurodevelopmental abnormalities such as migration defects at early time points [90] [91]; but later on, these mice develop cerebellar aberrations and axonal loss, which is reflected by motor impairment and lethargy [92].”

What the sources say

• Not checked yetcites [90] Huyghe S Schmalbruch H De Gendt K Verhoeven G Guillou F Van Veldhoven PP Baes M Peroxisomal multifunctional protein 2 is essential for lipid homeostasis in Sertoli cells and male fertility in mice Endocrinology 2006 147 2228 2236 16484321
• Not checked yetcites [91] Baes M Dewerchin M Janssen A Collen D Carmeliet P Generation of Pex5-loxP mice allowing the conditional elimination of peroxisomes Genesis 2002 32 177 178 11857813
• Not checked yetcites [92] Huyghe S Schmalbruch H Hulshagen L Veldhoven PV Baes M Hartmann D Peroxisomal multifunctional protein-2 deficiency causes motor deficits and glial lesions in the adult central nervous system Am J Pathol 2006 168 1321 1334 16565505 PMC1606565

In the paper

“Marked hypomyelination was detected already during the second to third postnatal week (probably due to insufficient formation of myelin) and was found in all brain regions (later probably also due to demyelination), together with axonal loss, reactive astrocytes as well as activated microglia and macrophages [73].”

What the sources say

• Not checked yetcites [73] Bottelbergs A Verheijden S Van Veldhoven PP Just W Devos R Baes M Peroxisome deficiency but not the defect in ether lipid synthesis causes activation of the innate immune system and axonal loss in the central nervous system J Neuroinflammation 2012 9 61 22458306 PMC3419640

In the paper

“This was surprising, because Pex5 deletion in astrocytes resulted in accumulation of VLCFA as well as reduced plasmalogen levels in the brain.”

What the sources say

• Not checked yetcites [76] Bottelbergs A Verheijden S Hulshagen L Gutmann DH Goebbels S Nave KA Kassmann C Baes M Axonal integrity in the absence of functional peroxisomes from projection neurons and astrocytes Glia 2010 58 1532 1543 20578053

In the paper

“A mouse model of DBP deficiency (here termed Mfp2 deficiency) has been described, in which VLCFA accumulate specifically in brain, and the degradation of branched-chain fatty acids as well as the maturation of bile acid precursors were disturbed [89]. Mfp2-deficient mice appear quite normal at birth but are severely growth-retarded during the lactation period.”

What the sources say

• Not checked yetcites [89] Baes M Huyghe S Carmeliet P Declercq PE Collen D Mannaerts GP Van Veldhoven PP Inactivation of the peroxisomal multifunctional protein-2 in mice impedes the degradation of not only 2-methyl-branched fatty acids and bile acid intermediates but also of very long chain fatty acids J Biol Chem 2000 275 16329 16336 10748062

In the paper

“However, young adult mice gradually developed impaired motor function and premature death due to axonal degeneration, progressive subcortical demyelination and neuroinflammation, starting at two to six months of age.”

What the sources say

• Not checked yetcites [75] Kassmann CM Lappe-Siefke C Baes M Brugger B Mildner A Werner HB Natt O Michaelis T Prinz M Frahm J Nave KA Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes Nat Genet 2007 39 969 976 17643102

In the paper

“Marked hypomyelination was detected already during the second to third postnatal week (probably due to insufficient formation of myelin) and was found in all brain regions (later probably also due to demyelination), together with axonal loss, reactive astrocytes as well as activated microglia and macrophages [73].”

What the sources say

• Not checked yetcites [73] Bottelbergs A Verheijden S Van Veldhoven PP Just W Devos R Baes M Peroxisome deficiency but not the defect in ether lipid synthesis causes activation of the innate immune system and axonal loss in the central nervous system J Neuroinflammation 2012 9 61 22458306 PMC3419640

In the paper

“All known human patients with bifunctional protein deficiency harbor mutations in the HSDI7B4 gene [83], whereas no patients with a mutation in the EHHADH gene, encoding LBP, have yet been identified.”

What the sources say

• Not checked yetcites [83] Ferdinandusse S Denis S Mooyer PA Dekker C Duran M Soorani-Lunsing RJ Boltshauser E Macaya A Gartner J Majoie CB Barth PG Clinical and biochemical spectrum of D-bifunctional protein deficiency Ann Neurol 2006 59 92 104 16278854

In the paper

“Because ABCD2 and ABCD3 as well as the peroxisomal β-oxidation enzymes are intact in X-ALD, only saturated straight-chain VLCFA accumulate, but to a variable extent in different cell types and tissues.”

In the paper

“It is intriguing that also Abcd1/Abcd2 double-deficient mice do not develop brain inflammation or demyelination [156], in spite of the finding that Abcd1/Abcd2 double-deficient peritoneal macrophages are metabolically much more severely affected than those from single transporter-deficient mice [157]. Also in these mice, the neuropathology is restricted mainly to axonopathy in the spinal cord and,”

What the sources say

• Not checked yetcites [156] Pujol A Ferrer I Camps C Metzger E Hindelang C Callizot N Ruiz M Pampols T Giros M Mandel JL Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy Hum Mol Genet 2004 13 2997 3006 15489218 source
• Not checked yetcites [157] Muneer Z Wiesinger C Voigtlander T Werner HB Berger J Forss-Petter S Abcd2 Is a strong modifier of the metabolic impairments in peritoneal macrophages of Abcd1-deficient mice PLoS One 2014 9 e108655 25255441 PMC4177892 source

In the paper

“in case of RCDP type 1, elevated plasma levels of phytanic acid have been detected [186].”

What the sources say

• Not checked yetcites [186] Hoefler G Hoefler S Watkins PA Chen WW Moser A Baldwin V McGillivary B Charrow J Friedman JM Rutledge L Biochemical abnormalities in rhizomelic chondrodysplasia punctata J Pediatr 1988 112 726 733 2452243

In the paper

“Mutations in the PHYH gene have been established as the genetic cause for classical Refsum disease (MIM #266500) [170, 171]. The 3-methyl branched-chain fatty acid phytanic acid, solely taken up from dietary sources, accumulates in patients with Refsum disease.”

What the sources say

• Not checked yetcites [170] Jansen GA Ofman R Ferdinandusse S Ijlst L Muijsers AO Skjeldal OH Stokke O Jakobs C Besley GT Wraith JE Wanders RJ Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene Nat Genet 1997 17 190 193 9326940
• Not checked yetcites [171] Jansen GA Hogenhout EM Ferdinandusse S Waterham HR Ofman R Jakobs C Skjeldal OH Wanders RJ Human phytanoyl-CoA hydroxylase: resolution of the gene structure and the molecular basis of Refsum’s disease Hum Mol Genet 2000 9 1195 1200 10767344

In the paper

“Encouraging results were obtained from a study applying an antioxidant cocktail consisting of vitamin E, N-acetylcystein and lipoic acid to aging Abcd1-deficient mice; this dietary treatment was sufficient to prevent the onset of locomotor disability and axonal damage [163]. In line with these findings, also oral administration of pioglitazone, an agonist of peroxisome proliferator-activated”

What the sources say

• Not checked yetcites [163] Lopez-Erauskin J Fourcade S Galino J Ruiz M Schluter A Naudi A Jove M Portero-Otin M Pamplona R Ferrer I Pujol A Antioxidants halt axonal degeneration in a mouse model of X-adrenoleukodystrophy Ann Neurol 2011 70 84 92 21786300 PMC3229843
• Not checked yetcites [164] Morato L Galino J Ruiz M Calingasan NY Starkov AA Dumont M Naudi A Martinez JJ Aubourg P Portero-Otin M Pamplona R Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy Brain 2013 136 2432 2443 23794606 PMC4550111

In the paper

“In a classical gene KO model, Acaa1b deficiency showed a very mild phenotype and hardly any accumulation of VLCFA, indicating a compensatory effect from Acaa1a and/or Scpx in mice [103]. In Scpx-deficient mice, methyl-branched-chain fatty acid catabolism is impaired resulting in a mild phenotype under standard conditions [104].”

What the sources say

• Not checked yetcites [103] Chevillard G Clemencet MC Latruffe N Nicolas-Frances V Targeted disruption of the peroxisomal thiolase B gene in mouse: a new model to study disorders related to peroxisomal lipid metabolism Biochimie 2004 86 849 856 15589695
• Not checked yetcites [104] Seedorf U Raabe M Ellinghaus P Kannenberg F Fobker M Engel T Denis S Wouters F Wirtz KW Wanders RJ Maeda N Defective peroxisomal catabolism of branched fatty acyl coenzyme A in mice lacking the sterol carrier protein-2/sterol carrier protein-x gene function Genes Dev 1998 12 1189 1201 9553048 PMC316706

In the paper

“Although X-ALD does not involve any developmental defect or delay, it is characterized by remarkable clinical heterogeneity. The main phenotypes are adrenomyeloneuropathy (AMN) and cerebral ALD (CALD), the devastating inflammatory and demyelinating form of X-ALD [120].”

What the sources say

• Not checked yetcites [120] Kemp S Berger J Aubourg P X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects Biochim Biophys Acta 2012 22483867 source

In the paper

“However, the extent to which the brain is affected varies remarkably between patients and many of the symptoms are restricted to the severer forms of the disease.”

In the paper

“Virtually all male patients with mutations in the ABCD1 gene eventually develop AMN, a slowly progressive myelopathy with typical onset in the third or fourth decade of life.”

In the paper

“The most typical are the eponymous shortening of the proximal long bones (rhizomelia) and epiphyseal stippling (chondrodysplasia punctata) as well as congenital cataracts, joint contractures and growth and developmental retardation [187].”

What the sources say

• Not checked yetcites [187] Braverman NE Moser AB Functions of plasmalogen lipids in health and disease Biochim Biophys Acta 2012 1822 1442 1452 22627108

In the paper

“Mental disability and delayed motor development are hallmarks of RCDP.”

In the paper

“Because standard mouse chow is very low in branched-chain fatty acids, Phyh-deficient mice have an unremarkable phenotype. However, dietary supplementation with 0.25% phytol (the precursor of phytanic acid) for three weeks or 0.1% phytol for six weeks caused ataxia, reflecting Purkinje cell loss and astrogliosis in the cerebellum, and peripheral neuropathy, as revealed by nerve conduction velocity”

What the sources say

• Not checked yetcites [175] Ferdinandusse S Zomer AW Komen JC van den Brink CE Thanos M Hamers FP Wanders RJ van der Saag PT Poll-The BT Brites P Ataxia with loss of Purkinje cells in a mouse model for Refsum disease Proc Natl Acad Sci U S A 2008 105 17712 17717 19004801 PMC2584743

In the paper

“RCDP type 1 (MIM #215100) is evoked by mutations in the gene encoding PEX7 [176–178], the cytosolic receptor for peroxisomal import of PTS2-containing proteins, whereas RCDP type 2 (MIM #222765) and type 3 (MIM #600121) are caused by mutations in the genes of the first two enzymes for biosynthesis of ether phospholipids, dihydroxyacetone phosphate acyltransferase (DHAPAT, DAPAT; encoded by the GNP”

What the sources say

• Not checked yetcites [176] Braverman N Steel G Obie C Moser A Moser H Gould SJ Valle D Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata Nat Genet 1997 15 369 376 9090381
• Not checked yetcites [177] Motley AM Hettema EH Hogenhout EM Brites P ten Asbroek AL Wijburg FA Baas F Heijmans HS Tabak HF Wanders RJ Distel B Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease caused by a non-functional PTS2 receptor Nat Genet 1997 15 377 380 9090382
• Not checked yetcites [178] Purdue PE Zhang JW Skoneczny M Lazarow PB Rhizomelic chondrodysplasia punctata is caused by deficiency of human PEX7, a homologue of the yeast PTS2 receptor Nat Genet 1997 15 381 384 9090383

In the paper

“In this active region, infiltration of macrophages, CD4+ and CD8 + cytotoxic T cells, as well as activated microglia and astrocytes can be observed [140]. This severe neuroinflammation probably causes the loss of oligodendrocytes, which die by cytolysis rather than by apoptosis [140].”

What the sources say

• Not checked yetcites [140] Ito M Blumberg BM Mock DJ Goodman AD Moser AB Moser HW Smith KD Powers JM Potential environmental and host participants in the early white matter lesion of adreno-leukodystrophy: morphologic evidence for CD8 cytotoxic T cells, cytolysis of oligodendrocytes, and CD1-mediated lipid antigen presentation J Neuropathol Exp Neurol 2001 60 1004 1019 11589421 source

In the paper

“In contrast, patients with a less severe disease course present with only some of the characteristic symptoms and can survive into young adulthood [192–194].”

What the sources say

• Not checked yetcites [192] White AL Modaff P Holland-Morris F Pauli RM Natural history of rhizomelic chondrodysplasia punctata Am J Med Genet A 2003 118A 332 342 12687664
• Not checked yetcites [193] Motley AM Brites P Gerez L Hogenhout E Haasjes J Benne R Tabak HF Wanders RJ Waterham HR Mutational spectrum in the PEX7 gene and functional analysis of mutant alleles in 78 patients with rhizomelic chondrodysplasia punctata type 1 Am J Hum Genet 2002 70 612 624 11781871 PMC384941
• Not checked yetcites [194] Poll-The BT Maroteaux P Narcy C Quetin P Guesnu M Wanders RJ Schutgens RB Saudubray JM A new type of chondrodysplasia punctata associated with peroxisomal dysfunction J Inherit Metab Dis 1991 14 361 363 1770792

In the paper

“Several studies have reported hypomyelination in different brain areas (neocortex, corpus callosum, cerebellum) of ether lipid-deficient mice [217,218], but no progressive demyelination as seen in several mouse models of Zellweger syndrome [73].”

What the sources say

• Not checked yetcites [217] Gorgas K Teigler A Komljenovic D Just WW The ether lipid-deficient mouse: tracking down plasmalogen functions Biochim Biophys Acta 2006 1763 1511 1526 17027098
• Not checked yetcites [218] Teigler A Komljenovic D Draguhn A Gorgas K Just WW Defects in myelination, paranode organization and Purkinje cell innervation in the ether lipid-deficient mouse cerebellum Hum Mol Genet 2009 18 1897 1908 19270340 PMC2722228
• Not checked yetcites [73] Bottelbergs A Verheijden S Van Veldhoven PP Just W Devos R Baes M Peroxisome deficiency but not the defect in ether lipid synthesis causes activation of the innate immune system and axonal loss in the central nervous system J Neuroinflammation 2012 9 61 22458306 PMC3419640

In the paper

“MR spectroscopy has also revealed elevated levels of mobile lipids, most likely caused by accumulation of long-chain acyl-CoAs, as well as a reduction of choline and the presence of acetate [199,209].”

What the sources say

• Not checked yetcites [199] Viola A Confort-Gouny S Ranjeva JP Chabrol B Raybaud C Vintila F Cozzone PJ MR imaging and MR spectroscopy in rhizomelic chondrodysplasia punctata AJNR Am J Neuroradiol 2002 23 480 483 11901023 PMC7975319
• Not checked yetcites [209] Alkan A Kutlu R Yakinci C Sigirci A Aslan M Sarac K Delayed myelination in a rhizomelic chondrodysplasia punctata case: MR spectroscopy findings Magn Reson Imaging 2003 21 77 80 12620550

In the paper

“From a metabolic point of view, MR spectroscopy of the brain has shown increased levels of myo-inositol, a marker for gliosis, in line with previous reports of gliosis in autopsy cases of RCDP [52,208].”

What the sources say

• Not checked yetcites [52] Powers JM The pathology of peroxisomal disorders with pathogenetic considerations J Neuropathol Exp Neurol 1995 54 710 719 7666061
• Not checked yetcites [208] Agamanolis DP Novak RW Rhizomelic chondrodysplasia punctata: report of a case with review of the literature and correlation with other peroxisomal disorders Pediatr Pathol Lab Med 1995 15 503 513 8597837

In the paper

“Remarkably, hypo- and dysmyelination in the CNS of ether lipid-deficient animals is accompanied by slight loss of axons and mild astrogliosis in some brain areas, whereas microgliosis, which has been reported in several RCDP cases, and the induction of inflammatory cytokines appear to be less pronounced [73].”

What the sources say

• Not checked yetcites [73] Bottelbergs A Verheijden S Van Veldhoven PP Just W Devos R Baes M Peroxisome deficiency but not the defect in ether lipid synthesis causes activation of the innate immune system and axonal loss in the central nervous system J Neuroinflammation 2012 9 61 22458306 PMC3419640

In the paper

“Also myelin of the PNS is affected in ether lipid-deficient mice. Deficiencies in myelination as well as Schwann cell development and differentiation are found [219] resulting in peripheral neuropathy, as judged by reduced motor neuron conduction velocity [220].”

What the sources say

• Not checked yetcites [219] da Silva TF Eira J Lopes AT Malheiro AR Sousa V Luoma A Avila RL Wanders RJ Just WW Kirschner DA Sousa MM Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination J Clin Invest 2014 124 2560 2570 24762439 PMC4038568
• Not checked yetcites [220] Brites P Mooyer PA El Mrabet L Waterham HR Wanders RJ Plasmalogens participate in very-long-chain fatty acid-induced pathology Brain 2009 132 482 492 19022859

In the paper

“MRI examination in children with RCDP has revealed varying pathologic features, although some cases, usually with a milder phenotype, with unremarkable MRI results are also found [195].”

What the sources say

• Not checked yetcites [195] Bams-Mengerink AM Majoie CB Duran M Wanders RJ Van Hove J Scheurer CD Barth PG Poll-The BT MRI of the brain and cervical spinal cord in rhizomelic chondrodysplasia punctata Neurology 2006 66 798 803 discussion 789 16567694

In the paper

“Consistently, most reports describe enlargement of ventricles and the subarachnoid space, abnormalities in white matter signal intensity and delayed supratentorial white matter myelination with frequent involvement of the parieto-occipital area [195–200].”

What the sources say

• Not checked yetcites [195] Bams-Mengerink AM Majoie CB Duran M Wanders RJ Van Hove J Scheurer CD Barth PG Poll-The BT MRI of the brain and cervical spinal cord in rhizomelic chondrodysplasia punctata Neurology 2006 66 798 803 discussion 789 16567694
• Not checked yetcites [196] Sztriha L Al-Gazali LI Wanders RJ Ofman R Nork M Lestringant GG Abnormal myelin formation in rhizomelic chondrodysplasia punctata type 2 (DHAPAT-deficiency) Dev Med Child Neurol 2000 42 492 495 10972423
• Not checked yetcites [197] Karabayir N Keskindemirci G Adal E Korkmaz O A case of rhizomelic chondrodysplasia punctata in newborn Case Rep Med 2014 2014 879679 24715923 PMC3970257
• Not checked yetcites [198] Sastrowijoto SH Vandenberghe K Moerman P Lauweryns JM Fryns JP Prenatal ultrasound diagnosis of rhizomelic chondrodysplasia punctata in a primigravida Prenat Diagn 1994 14 770 776 7991519
• Not checked yetcites [199] Viola A Confort-Gouny S Ranjeva JP Chabrol B Raybaud C Vintila F Cozzone PJ MR imaging and MR spectroscopy in rhizomelic chondrodysplasia punctata AJNR Am J Neuroradiol 2002 23 480 483 11901023 PMC7975319
• Not checked yetcites [200] Goh S Neuroimaging features in a neonate with rhizomelic chondrodysplasia punctata Pediatr. Neurol 2007 37 382 384 17950430

In the paper

“However, neuroinflammation with marked microglia activation was observed upon combined deficiency of Pex7 and Abcd1 in 11-months-old mice of mixed background (Swiss Webster and C57BL/6J:129S1) [220] suggesting that ether lipid deficiency has little effect on immune cell activation under basal conditions but more drastic consequences in the presence of an additional immunostimulatory factor.”

What the sources say

• Not checked yetcites [220] Brites P Mooyer PA El Mrabet L Waterham HR Wanders RJ Plasmalogens participate in very-long-chain fatty acid-induced pathology Brain 2009 132 482 492 19022859

In the paper

“Also epileptic seizures are very common but non-specific; seizure type and frequency vary considerably and even affected children with multiple seizure types have been reported [191,192].”

What the sources say

• Not checked yetcites [191] Bams-Mengerink AM Koelman JH Waterham H Barth PG Poll-The BT The neurology of rhizomelic chondrodysplasia punctata Orphanet J Rare Dis 2013 8 174 24172221 PMC4228450
• Not checked yetcites [192] White AL Modaff P Holland-Morris F Pauli RM Natural history of rhizomelic chondrodysplasia punctata Am J Med Genet A 2003 118A 332 342 12687664

In the paper

“Currently, gene KO mouse models exist for RCDP types 1–3 (Pex 7, Gnpat and Agps KO mice, respectively) [210–212], of which the first two models have been extensively characterized.”

What the sources say

• Not checked yetcites [210] Brites P Motley AM Gressens P Mooyer PA Ploegaert I Everts V Evrard P Carmeliet P Dewerchin M Schoonjans L Duran M Impaired neuronal migration and endochondral ossification in Pex7 knockout mice: a model for rhizomelic chondrodysplasia punctata Hum Mol Genet 2003 12 2255 2267 12915479
• Not checked yetcites [211] Rodemer C Thai TP Brugger B Kaercher T Werner H Nave KA Wieland F Gorgas K Just WW Inactivation of ether lipid biosynthesis causes male infertility, defects in eye development and optic nerve hypoplasia in mice Hum Mol Genet 2003 12 1881 1895 12874108
• Not checked yetcites [212] Liegel RP Ronchetti A Sidjanin DJ Alkylglycerone phosphate synthase (AGPS) deficient mice: models for rhizomelic chondrodysplasia punctate type 3 (RCDP3) malformation syndrome Mol Genet Metab Rep 2014 1 299 311 25197626 PMC4151185

In the paper

“Microscopy studies revealed structural abnormalities in the innervation of Purkinje cells by parallel fibers and climbing fibers as well as axonal swellings with accumulation of smooth ER-like structures in Purkinje cells [218].”

What the sources say

• Not checked yetcites [218] Teigler A Komljenovic D Draguhn A Gorgas K Just WW Defects in myelination, paranode organization and Purkinje cell innervation in the ether lipid-deficient mouse cerebellum Hum Mol Genet 2009 18 1897 1908 19270340 PMC2722228

In the paper

“Neuronal migration defects never reach the extent of those observed in Zellweger syndrome (see Fig. 2A), but several cases with dysplastic olivary bodies have been reported [202,206].”

What the sources say

• Not checked yetcites [202] Powers JM Kenjarski TP Moser AB Moser HW Cerebellar atrophy in chronic rhizomelic chondrodysplasia punctata: a potential role for phytanic acid and calcium in the death of its Purkinje cells Acta Neuropathol 1999 98 129 134 10442551
• Not checked yetcites [206] Poulos A Sheffield L Sharp P Sherwood G Johnson D Beckman K Fellenberg AJ Wraith JE Chow CW Usher S Rhizomelic chondrodysplasia punctata: clinical, pathologic, and biochemical findings in two patients J Pediatr 1988 113 685 690 3171792

In the paper

“Also, a migration defect of granule cell precursors [218] and increased numbers of apoptotic cells in the external granule layer [225] were found.”

What the sources say

• Not checked yetcites [218] Teigler A Komljenovic D Draguhn A Gorgas K Just WW Defects in myelination, paranode organization and Purkinje cell innervation in the ether lipid-deficient mouse cerebellum Hum Mol Genet 2009 18 1897 1908 19270340 PMC2722228
• Not checked yetcites [225] Krysko O Bottelbergs A Van Veldhoven P Baes M Combined deficiency of peroxisomal beta-oxidation and ether lipid synthesis in mice causes only minor cortical neuronal migration defects but severe hypotonia Mol Genet Metab 2010 100 71 76 20202875

In the paper

“Furthermore, hypoplasia of the optic nerve, microphtalmia, a persistent hyaloid artery [211] and abnormal vascularization [229] were detected in Gnpat KO mice.”

What the sources say

• Not checked yetcites [211] Rodemer C Thai TP Brugger B Kaercher T Werner H Nave KA Wieland F Gorgas K Just WW Inactivation of ether lipid biosynthesis causes male infertility, defects in eye development and optic nerve hypoplasia in mice Hum Mol Genet 2003 12 1881 1895 12874108
• Not checked yetcites [229] Saab S Buteau B Leclere L Bron AM Creuzot-Garcher CP Bretillon L Acar N Involvement of plasmalogens in post-natal retinal vascular development PLoS One 2014 9 e101076 24963632 PMC4071069

In the paper

“Remarkably, although similar techniques were used, no such alterations could be detected in the brains of Gnpat KO mice [225], pointing towards a role of phytanic acid in the development of these migration defects or potential differences in the background strains of the mice used in the different studies.”

What the sources say

• Not checked yetcites [225] Krysko O Bottelbergs A Van Veldhoven P Baes M Combined deficiency of peroxisomal beta-oxidation and ether lipid synthesis in mice causes only minor cortical neuronal migration defects but severe hypotonia Mol Genet Metab 2010 100 71 76 20202875

In the paper

“This goes along with decreased ATP content and an inability of synaptosomal respiration to adapt to the higher energy requirements of depolarization, thereby offering a potential explanation for the defects in synaptosomal neurotransmitter release [40] (Fig. 3B).”

What the sources say

• Not checked yetcites [40] Brodde A Teigler A Brugger B Lehmann WD Wieland F Berger J Just WW Impaired neurotransmission in ether lipid-deficient nerve terminals Hum Mol Genet 2012 21 2713 2724 22403185 PMC4880048

In the paper

“Furthermore, it has been suggested that deficiency in plasmalogens impairs membrane rafts (formerly termed lipid rafts) [211], small membrane domains that organize various cellular processes [236,237] and are enriched in plasmalogens [238].”

What the sources say

• Not checked yetcites [211] Rodemer C Thai TP Brugger B Kaercher T Werner H Nave KA Wieland F Gorgas K Just WW Inactivation of ether lipid biosynthesis causes male infertility, defects in eye development and optic nerve hypoplasia in mice Hum Mol Genet 2003 12 1881 1895 12874108
• Not checked yetcites [236] Pike LJ Rafts defined: a report on the Keystone Symposium on Lipid Rafts and Cell Function J Lipid Res 2006 47 1597 1598 16645198
• Not checked yetcites [237] Simons K Ikonen E Functional rafts in cell membranes Nature 1997 387 569 572 9177342
• Not checked yetcites [238] Pike LJ Han X Chung KN Gross RW Lipid rafts are enriched in arachidonic acid and plasmenylethanolamine and their composition is independent of caveolin-1 expression: a quantitative electrospray ionization/mass spectrometric analysis Biochemistry 2002 41 2075 2088 11827555

In the paper

“Recently, a defect in the activation and downstream signaling of AKT was proposed to be responsible for the myelination deficit in the PNS of ether lipid-deficient animals [219].”

What the sources say

• Not checked yetcites [219] da Silva TF Eira J Lopes AT Malheiro AR Sousa V Luoma A Avila RL Wanders RJ Just WW Kirschner DA Sousa MM Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination J Clin Invest 2014 124 2560 2570 24762439 PMC4038568