Inactivation of the peroxisomal ABCD2 transporter in the mouse leads to late-onset ataxia involving mitochondria, Golgi and endoplasmic reticulum damage
Open accessAbstract
ATP-binding cassette (ABC) transporters facilitate unidirectional translocation of chemically diverse substances, ranging from peptides to lipids, across cell or organelle membranes. In peroxisomes, a subfamily of four ABC transporters (ABCD1 to ABCD4) has been related to fatty acid transport, because patients with mutations in ABCD1 (ALD gene) suffer from X-linked adrenoleukodystrophy (X-ALD), a disease characterized by an accumulation of very-long-chain fatty acids (VLCFAs). Inactivation in the mouse of the abcd1 gene leads to a late-onset neurodegenerative condition, comparable to the late-onset form of X-ALD [Pujol, A., Hindelang, C., Callizot, N., Bartsch, U., Schachner, M. and Mandel, J.L. (2002) Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy. Hum. Mol. Genet., 11, 499-505.]. In the present work, we have generated and characterized a mouse deficient for abcd2, the closest paralog to abcd1. The main pathological feature in abcd2-/- mice is a late-onset cerebellar and sensory ataxia, with loss of cerebellar Purkinje cells and dorsal root ganglia cell degeneration, correlating with accumulation of VLCFAs in the latter cellular population. Axonal degeneration was present in dorsal and ventral columns in spinal cord. We have identified mitochondrial, Golgi and endoplasmic reticulum damage as the underlying pathological mechanism, thus providing evidence of a disturbed organelle cross-talk, which may be at the…
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- Premisecitation
Inactivation of abcd2 does not lead to accumulation of VLCFAs in nervous tissues.
“inactivation of abcd2 does not lead to accumulation of VLCFAs in nervous tissues”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [18] Pujol, A., Ferrer, I., Camps, C., Metzger, E., Hindelang, C., Callizot, N., Ruiz, M., Pampols, T., Giros, M. and Mandel, J.L. (2004) Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy. Hum. Mol. Genet., 13, 2997–3006. source
- Findingown data
C24:0 levels are higher in double mutant fibroblasts than in wild-type or abcd1-/- fibroblasts (P < 0.01).
“C24:0 levels are higher in double mutants than in wild-type or abcd1-fibroblasts (P , 0.01).”
Quote in the paperSubstantial claim - Findingown data
Axonal degeneration is present in dorsal and ventral columns in the spinal cord of abcd2-/- mice.
“Axonal degeneration was present in dorsal and ventral columns in spinal cord.”
Quote in the paperSubstantial claim - Findingown data
VLCFA accumulation in dorsal root ganglia correlates with dorsal root ganglia cell degeneration in abcd2-/- mice.
“correlating with accumulation of VLCFAs in the latter cellular population”
Quote in the paperSubstantial claim - Findingnone given
All pathological changes noticed by ultrastructural or immunohistochemical techniques in abcd2-/- mice at DRGs, spinal cords and cerebellar sites were presented in the same extent, intensity and age by abcd1 deficient mice.
“all the pathological changes noticed by ultrastructural or immunohistochemical techniques in abcd22/2 mice at DRGs, spinal cords and cerebellar sites were presented in the same extent, intensity and age by abcd1 deficient mice.”
Quote in the paperSubstantial claim
- Findingown data
Double mutant fibroblasts accumulate higher levels of C26:0 than abcd1-/- fibroblasts (P < 0.001).
“double mutant fibroblasts accumulate higher levels of C26:0 than abcd1-fibroblasts (P , 0.001).”
Quote in the paperSubstantial claim - Findingown data
At 12 months of age, abcd2-/- mice present lower amplitude of the H-wave than their wild-type littermates.
“At 12 months of age, abcd22/2 mice present lower amplitude of the H-wave than their wild-type littermates”
Quote in the paperSubstantial claim - Findingown data
Disturbed endoplasmic reticulum and Golgi apparatus, with dilatation and fragmentation of channels and cisterns, were observed in abcd2-/- mice.
“We observed disturbed endoplasmic reticulum and Golgi apparatus, with dilatation and fragmentation of channels and cisterns”
Quote in the paperSubstantial claim - Findingown data
At 12 months of age, abcd2-/- null mice were significantly more active than their wild-type littermates in the open field.
“abcd22/2 null mice were significantly more active than their wild-type littermates.”
Quote in the paperNot a substantial claim - Findingown data
Mice lacking ALDRP displayed progressive behavioral deficits from 12 months onwards.
“mice lacking ALDRP displayed progressive behavioral deficits, consistent with ongoing neural degeneration from 12 months onwards.”
Quote in the paperSubstantial claim - Findingown data
In spinal cord dorsal and ventral columns, histological abnormalities not demonstrable at 12 months became evident in abcd2-/- mice at 20 months of age.
“In spinal cord dorsal and ventral columns, histological abnormalities not demonstrable at 12 months of age became evident in abcd22/2 mice at 20 months of age.”
Quote in the paperSubstantial claim - Findingown data
At 20 months of age, gaps in the Purkinje cell monolayer were detected in Nissl-stained sections of abcd2-/- cerebellum.
“we detected gaps in the Purkinje cell monolayer in Nissl-stained sections”
Quote in the paperSubstantial claim - Findingown data
Quantitative RT-PCR confirmed the absence of full-length abcd2 mRNA in abcd2-/- mice.
“Quantitative RT-PCR confirmed the absence of full-length abcd2 mRNA”
Quote in the paperSubstantial claim - Findingown data
abcd2-/- mice have a late-onset cerebellar and sensory ataxia.
“The main pathological feature in abcd22/2 mice is a late-onset cerebellar and sensory ataxia”
Quote in the paperSubstantial claim - Findingown data
abcd2-/- mice have loss of cerebellar Purkinje cells.
“with loss of cerebellar Purkinje cells”
Quote in the paperSubstantial claim - Findingown data
At 12 months of age, abcd2-/- mice displayed marked impairment in rotarod performance compared with wild-type littermates (P < 0.01 by ANOVA).
“When compared with wild-type littermates at 12 months of age, abcd22/2 mice displayed a marked impairment in their performance during 4 days trial on the rotating rod set at an accelerating speed (P , 0.01 by ANOVA)”
Quote in the paperSubstantial claim - Findingown data
A significant number of mitochondria in abcd2-/- mice showed degenerative images and contained lipidic inclusions.
“A significant number of mitochondria showed degenerative images and contained lipidic inclusions”
Quote in the paperSubstantial claim - Findingown data
At 15 months of age, the time required for abcd1-/-/abcd2-/- double mutant mice to reach a platform along a balance bar was significantly increased (P < 0.001).
“At 15 months of age, the time required for mice to reach a platform along a balance bar was significantly increased in abcd12/abcd22/2 double mutants (P , 0.001)”
Quote in the paperSubstantial claim - Findingown data
Absence of the abcd2 gene was not accompanied by compensatory increases of the abcd1 gene in CNS, PNS, adrenal gland and testis.
“Absence of the abcd2 gene was not accompanied by compensatory increases of its closest paralog, the abcd1 gene”
Quote in the paperNot a substantial claim - Findingown data
No difference in muscular strength was demonstrated between mutants and controls.
“No difference could be demonstrated between mutants and controls”
Quote in the paperSubstantial claim - Findingown data
Electron microscopy revealed a specific pattern of degeneration in abcd2-/- mice, more evident at 20 months of age.
“electron microscopy examination revealed a specific pattern of degeneration, more evident at 20 months of age.”
Quote in the paperSubstantial claim - Findingown data
Western blots showed complete absence of ALDRP protein in all tissues of abcd2-/- mice.
“Western blots showed a complete absence of the protein in all tissues of abcd22/2 mice”
Quote in the paperSubstantial claim - Findingown data
abcd2-/- mice have dorsal root ganglia cell degeneration.
“dorsal root ganglia cell degeneration”
Quote in the paperSubstantial claim - Findingown data
C26:0 accumulates in DRGs from abcd2-/- mice (P < 0.002).
“We could indeed detect an accumulation of C26:0 in DRGs from abcd22/2 mice (Fig. 3I and J, P , 0.002).”
Quote in the paperSubstantial claim - Findingown data
Reactive astrogliosis is observed in aldr2/2 mice when compared with littermate controls.
“Reactive astrogliosis is observed in aldr2/2 mice when compared with littermate controls.”
Quote in the paperNot a substantial claim - Findingown data
In aldr2/2 mice at 20 months, ganglion cells show mitochondria with paracristallin profile resulting from juxtaposition of parallel-stacked cristae.
“In a ganglionar cell, mitochondria (m) with paracristallin profile (arrow) resulting from the juxtaposition of parallel-stacked cristae.”
Quote in the paperNot a substantial claim - Findingown data
In aldr2/2 mice at 20 months, strong reduction of non-phosphorylated neurofilaments in Purkinje cells was seen by staining with anti-SMI32.
“Strong reduction of non-phosphorylated neurofilaments in Purkinje cells was seen by staining with anti-SMI32.”
Quote in the paperNot a substantial claim - Findingown data
In aldr2/2 mice at 20 months, DRG cells show a high number of zebra bodies filling satellite cells.
“High number of zebra bodies filling up a satellite cell (s).”
Quote in the paperNot a substantial claim - Findingown data
Adult fibroblasts from Ald2 and double mutant mice show similar reduction of C26:0 beta-oxidation to 60% of the wild-type level (P<0.0008).
“Ald2 and double mutant fibroblasts show similar reduction to 60% of the wild-type level (P , 0.0008).”
Quote in the paperNot a substantial claim - Findingown data
In aldr2/2 mice at 20 months, cerebellar pathology includes loss of Purkinje cell somata evidenced by Nissl staining.
“Loss of Purkinje cell somata evidenced by Nissl staining (arrowheads).”
Quote in the paperSubstantial claim - Findingown data
In aldr2/2 mice at 20 months, axolemma decompactation is observed.
“Decompactation of axolemma (arrow).”
Quote in the paperNot a substantial claim - Findingown data
Saturated VLCFA levels are significantly different versus wild-type in adult fibroblasts and DRG samples.
“Quantification of saturated VLCFA levels by ESI-MS in adult fibroblasts and DRG samples, expressed as micromoles per milligram of protein.Wild-type levels have been set to 100.(Single asterisk) Significant difference versus wild-type.”
Quote in the paperSubstantial claim - Findingown data
Synaptophysin and APP deposits are ubiquitinated.
“Synaptophysin and APP deposits are ubiquitinated (K and L).”
Quote in the paperNot a substantial claim - Findingown data
In aldr2/2 mice at 20 months, ganglion cells contain polymorphous residual and zebra-like bodies.
“Polymorphous residual and zebra-like bodies in cytoplasm of a ganglion cell (arrows).”
Quote in the paperNot a substantial claim - Findingown data
In aldr2/2 mice at 20 months, spinal cord ventral horn gray matter shows axonal sprouting within a large axon filled with neurofilaments surrounded by myelin sheath and lipid droplet.
“Axonal sprouting within a large axon filled with neurofilaments (nf) surrounded by myelin sheath (ms), lipid droplet (ld).”
Quote in the paperNot a substantial claim - Findingown data
APP deposits are seen in axonal swellings in aldr2/2 mice.
“APP deposits are seen in axonal swellings in aldr2/2 mice.”
Quote in the paperNot a substantial claim - Findingown data
In aldr2/2 mice at 20 months, satellite cells contain mitochondria with lipidic residual bodies.
“Mitochondria containing lipidic residual bodies in satellite cells.”
Quote in the paperNot a substantial claim - Findingown data
In aldr2/2 mice at 20 months, empty myelinated fibers containing myelin bodies are observed.
“An empty myelinated fiber containing two myelin bodies.”
Quote in the paperNot a substantial claim - Findingown data
Aldr2/2 mice slipped away more often than their wild-type littermates and ald-mice.
“Aldr2/2 slipped away more often than their wild-type littermates and ald-mice.”
Quote in the paperSubstantial claim - Findingown data
Open-field experiments showed lack of habituation of aldr2/2 mutants at 12 months of age (n=8 wt and n=12 aldr2/2).
“Open-field experiments showing lack of habituation of aldr2/2 mutants at 12 months of age (n ¼ 8 wt and n ¼ 12 aldr2/2).”
Quote in the paperSubstantial claim - Findingown data
Lipidic debris of myelin is present in aldr2/2 mice, as revealed with Sudan black.
“This is accompanied by lipidic debris of myelin, as revealed with Sudan black in (G and H).”
Quote in the paperNot a substantial claim - Findingown data
In aldr2/2 mice at 20 months, spinal cord shows dense, degenerating axoplasm focally surrounded by distorted myelin.
“Dense, degenerating axoplasm focally surrounded by distorted myelin.”
Quote in the paperSubstantial claim - Findingown data
In aldr2/2 mice at 20 months, degenerating axoplasm contains tubulo-vesicular inclusions and fragmented smooth ER.
“Higher magnification of the region within the square in (C), showing tubulo-vesicular inclusions (tvi) and fragmented smooth ER (asterisk).”
Quote in the paperSubstantial claim - Findingown data
Abnormal fibers filled with synaptophysin are found in aldr2/2 mice.
“In (I and J), abnormal fibers filled with synaptophysin are found in aldr2/2 mice.”
Quote in the paperNot a substantial claim - Findingown data
In aldr2/2 mice, sciatic nerve shows axonal sprouting consistent with axonal regeneration.
“Axonal sprouting consistent with axonal regeneration in sciatic nerve.”
Quote in the paperNot a substantial claim - Interpretationcitation
ALDRP is able to take over from ALDP, at least when overexpressed.
“which indicates that ALDRP is indeed able to take over from ALDP, at least when overexpressed.”
Quote in the paperNot a substantial claim - Interpretationown data
abcd2 is widely expressed in different types of neuronal populations, from embryonic sensitive neurons of DRGs to mature differentiated spinal motor neurons.
“In summary, abcd2 is widely expressed in different types of neuronal populations, from embryonic sensitive neurons of DRGs to mature differentiated spinal motor neurons.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The increased open-field activity of abcd2-/- mice indicates a lack of habituation capacity to a new environment.
“This finding is indicative of a lack of habituation capacity to a new environment.”
Quote in the paperNot a substantial claim - Interpretationown data
There is compelling evidence of a redundant biochemical function between ALDP and ALDRP in the mouse.
“we present compelling evidence of a redundant biochemical function between the two transporters in the mouse.”
Quote in the paperSubstantial claim - Interpretationown data
Large proprioceptive sensory neurons at DRG or their afferents are functionally defective in abcd2-/- mice.
“These results indicate that the large proprioceptive sensory neurons at DRG or their afferents are functionally defective”
Quote in the paperSubstantial claim - Interpretationown data
In DRGs, abcd2 seems to play the same role regarding C26:0 import/catabolism that abcd1 plays in most tissues.
“Thus, in DRGs, abcd2 seems to play the same role regarding C26:0 import/catabolism that abcd1 plays in most tissues.”
Quote in the paperSubstantial claim - Interpretationown data
Mitochondrial, Golgi and endoplasmic reticulum damage is the underlying pathological mechanism in abcd2-/- mice.
“We have identified mitochondrial, Golgi and endoplasmic reticulum damage as the underlying pathological mechanism”
Quote in the paperSubstantial claim - Interpretationown data
abcd2 might cooperate or compensate to some extent for abcd1 loss of function.
“This suggests that abcd2 might cooperate or compensate to some extent for abcd1 loss of function.”
Quote in the paperSubstantial claim - Interpretationreasoning
Disturbed organelle cross-talk may be at the origin of the pathological cascade in abcd2-/- mice.
“providing evidence of a disturbed organelle cross-talk, which may be at the origin”
Quote in the paperSubstantial claim - Interpretationown data
Accumulation of VLCFAs in DRGs of abcd2-/- mice may increase the vulnerability of this particular cellular population to neurodegeneration.
“Thus, accumulation of VLCFAs in DRGs of abcd22/2 mice may increase the vulnerability to this particular cellular population to neurodegeneration.”
Quote in the paperSubstantial claim - Premisecitation
Covalently bound fatty acids contribute to the tertiary structure of PLP in aqueous medium.
“Because covalently bound fatty acids contribute to the tertiary structure of PLP in aqueous medium (50), this altered fatty acid composition may influence its physical or biological properties, compromising stability of PLP itself or its insertion in the myelin sheath.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [50] Bizzozero, O.A. and Lees, M.B. (1986) Fatty acid acylation of rat brain myelin proteolipid protein in vitro: identification of the lipid donor. J. Neurochem., 46, 630–636. source
- Interpretationown data
Aldr2/2 mice present a progressive neurological phenotype.
“Aldr2/2 mice present a progressive neurological phenotype.”
Quote in the paperSubstantial claim - Premisecitation
In adrenoleukodystrophy patients, the proportions of saturated VLCFAs bound to PLP are increased at the expense of oleic acid.
“In adrenoleukodystrophy patients, the proportions of saturated VLCFAs bound to PLP have been found to be increased at the expense of oleic acid (49).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [49] Bizzozero, O.A., Zuniga, G. and Lees, M.B. (1991) Fatty acid composition of human myelin proteolipid protein in peroxisomal disorders. J. Neurochem., 56, 872–878. source
- Interpretationown data
The absence of H-wave is aldr dependent.
“The absence of H-wave is aldr dependent.”
Quote in the paperSubstantial claim - Study design and conductown data
Southern blot analysis demonstrated homologous recombination at the Abcd2 locus in mouse tail genomic DNA.
“Southern blot analysis demonstrating homologous recombination at the Abcd2 locus in mouse tail genomic DNA.”
Quote in the paperSubstantial claim
- May combine two claims. 15
- Classified as probably not a substantial claim. 16
- The quote only partly states this claim. 2
May combine two claims.
PremisecitationStable overexpression of abcd2 by transgenesis in the ALD knockout mouse prevents accumulation of VLCFAs and the onset of neurological phenotype.
“its stable overexpression by transgenesis in the ALD knoc-kout mouse prevents accumulation of VLCFAs as well as the onset of neurological phenotype”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [18] Pujol, A., Ferrer, I., Camps, C., Metzger, E., Hindelang, C., Callizot, N., Ruiz, M., Pampols, T., Giros, M. and Mandel, J.L. (2004) Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy. Hum. Mol. Genet., 13, 2997–3006. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRecent evidence indicates a severe impairment of fast axonal transport system in the PLP/DM20 deficient mouse.
“Indeed, recent evidence indicates a severe impairment of fast axonal transport system in the PLP/DM20 deficient mouse (51), thus underscoring the importance of a healthy membrane for axonal function.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [51] Edgar, J.M., McLaughlin, M., Yool, D., Zhang, S.C., Fowler, J.H., Montague, P., Barrie, J.A., McCulloch, M.C., Duncan, I.D., Garbern, J. et al. (2004) Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia. J. Cell Biol., 166, 121–131. source
May combine two claims.
Findingown dataMice lacking abcd2 were delivered in expected Mendelian ratios, were viable and fertile, and did not show obvious abnormalities in development, behavior or gross morphology of the nervous system up to 6 months.
“Mice lacking the abcd2 gene were delivered in expected Mendelian ratios, were viable and fertile and did not show any obvious abnormalities in development, behavior or gross morphology of the nervous system up to 6 months”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn adult fibroblasts, lack of ALDRP is neither translated into accumulation of VLCFAs nor into a decrease of C26:0 beta-oxidation capacity.
“lack of ALDRP is neither translated into an accumulation of VLCFAs nor into a decrease of C26:0 b-oxidation capacity”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDouble mutants showed a more severe involvement and earlier onset of pathological signs, evidenced from 12 months onwards.
“Double mutants showed a more severe involvement and earlier onset of pathological signs, evidenced from 12 months onwards.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingnone givenThe offspring obeyed Mendelian ratios.
“the offspring obeyed Mendelian ratios.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn aldr2/2 mice at 20 months, non-myelinated fibers show enlargement with accumulation of organelles, and myelinated degenerating axons show decompactation of axolemma.
“At the image center, enlargement of a non-myelinated fiber, with accumulation of organelles.Note myelinated degenerating axons, with decompactation of axolemma (asterisk).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataBy the fourth trial, control animals ran the bar with not more than two slips.
“By the fourth trial, control animals ran the bar with not more than two slips.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataIn adult stages (weeks 5-6), aldr is expressed in interneurons of pons and spinal cord.
“In adult stages (weeks 5-6), aldr is expressed in interneurons of pons (G) and spinal cord (H).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe abcd2-/- mice were generated by inactivation of the abcd2 gene by classic homologous recombination.
“The abcd2 -/ -mice were generated by inactivation of the abcd2 gene by classic homologous recombination.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe ald gene exhibits a low and ubiquitous expression pattern throughout embryonic development and adult pons and spinal cord.
“In contrast, the ald gene exhibits a low and ubiquitous expression pattern, throughout embryonic development (B and D) and adult pons (I) and spinal cord (J).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn aldr2/2 mice at 20 months, axonal degeneration with involution of cellular organelles, formation of fibrillar body and myelin-like bodies, and numerous vacuoles is observed.
“Axonal degeneration: involution of the cellular organites with the formation of a fibrillar body (f) and myelin-like bodies (arrow); numerous vacuoles.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn aldr2/2 mice at 20 months, motor neuron cell bodies show hypertrophy of abnormal Golgi cisternae associated with fragmented smooth ER, and mitochondrial enlargement and densification of cristae.
“Motor neuron cell body with hypertrophy of abnormal Golgi (g) cisternae associated to fragmented smooth ER (asterisk).Mitochondrial enlargement and densification of cristae (arrows).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn aldr2/2 mice at 20 months, neurons contain lamellar bodies derived from altered Golgi and rough endoplasmic reticulum, and mitochondria with tubular cristae and ring-shaped alteration.
“In neurons, lamellar bodies derived from altered Golgi (g) and rough endoplasmic reticulum (arrows).Note mitochondria with tubular cristae (asterisk) and ring-shaped alteration (white arrow).”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataIn aldr2/2 mice at 20 months, focal loss of staining with anti-calbindin D28K is observed.
“Focal loss of staining with anti-calbindin D28K in the aldr2/2 mice.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataDouble mutant animals show delayed time to cross the bar and increased number of slips.
“Double mutant animals show delayed time to cross the bar and increased number of slips.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataIn aldr2/2 mice at 20 months, focal upregulations of GFAP expression are observed.
“Focal upregulations of GFAP expression in aldr2/2.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataProliferative neurons in cortex and neuro-olfactive epithelium are strongly positive for aldr at E14 and 5.
“Proliferative neurons in cortex (C and E) and neuro-olfactive epitelium (F) are strongly positive for aldr at E14 and 5.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataAldr is strongly expressed in DRGs at E11 and 5.
“Aldr is strongly expressed in DRGs at E11 and 5.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn aldr2/2 mice at 20 months, DRG ganglion cells show abnormal mitochondria with a lipid droplet and circular cristae, and fragmentation of Golgi cisternae.
“Abnormal mitochondria with a lipid droplet and circular cristae in a ganglion cell (m).Fragmentation of Golgi cisternae (g).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn aldr2/2 mice at 20 months, remnants of Golgi apparatus in form of lamellae are observed in a zone with small smooth ER vacuoles, and lamellated bodies within an axonal fiber.
“Remnants of the Golgi apparatus in the form of lamellae (arrows), in a zone with small smooth ER vacuoles.Two lamellated bodies within an axonal fiber (open arrows).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThree recombinant clones out of 302 resistant to neomycin were obtained and injected into blastocysts from C57BL/6 mice.
“We obtained three recombinant clones, out of 302, resistant to neomycin, which were injected into blastocysts from C57BL/6 mice.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn aldr2/2 mice at 20 months, Schwann cells contain myelin remnants resulting in fibrillar and granular body, and axolemma decompactation.
“Myelin remnants in the Schwann cell, resulting in a fibrillar and granular body (f).Axolemma decompactation (arrow).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationInactivation of the abcd1 gene in the mouse leads to a late-onset neurodegenerative condition comparable to the late-onset form of X-ALD.
“Inactivation in the mouse of the abcd1 gene leads to a late-onset neurodegenerative condition, comparable to the late-onset form of X-ALD”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Pujol, A., Hindelang, C., Callizot, N., Bartsch, U., Schachner, M. and Mandel, J.L. (2002)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
InterpretationreasoningTaking all pathological findings together, abcd2-/- mice develop a late-onset spinocerebellar ataxia, with impaired proprioception most likely due to neuronal degenerative processes at the DRG level or to synaptic defects in the spinal cord.
“Taking all pathological findings together, we conclude that abcd22/2 mice develop a lateonset spinocerebellar ataxia, with impaired propioception most likely due to neuronal degenerative processes at the DRG level or to synaptic defects in spinal cord.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationDefective mitochondria may lead to a failure of ATP-dependent axoplasmic transport with consequent dying-back axonal degeneration.
“Defective mitochondria may lead to a failure of ATP-dependent axoplasmic transport with consequent 'dying-back' axonal degeneration.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMutations in ABCD1 result in X-linked adrenoleukodystrophy/adrenomyeloneuropathy (X-ALD/AMN).
“Mutations in ABCD1 results in X-linked adrenoleukodystrophy/adrenomyeloneuropathy (X-ALD/AMN) (12).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Mosser, J., Douar, A.M., Sarde, C.O., Kioschis, P., Feil, R., Moser, H., Poustka, A.M., Mandel, J.L. and Aubourg, P. (1993) Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature, 361, 726–730. source
May combine two claims.
InterpretationreasoningThe composition, maintenance or recycling process of myelin and neuronal/axonal membrane might be disturbed in the ALD and ALDR models, leading to impaired axono-glia communication that would be detrimental for both interconnected compartments.
“We propose that the composition, maintenance or recycling process of myelin and neuronal/axonal membrane might be disturbed in the ALD and ALDR models, leading to impaired axono-glia communication, which would be detrimental for both interconnected compartments.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationVLCFA levels are increased in X-ALD brain gangliosides.
“VLCFAs levels have been found to be increased in X-ALD brain gangliosides (48), which might contribute to pathogenesis.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [48] Igarashi, M., Schaumburg, H.H., Powers, J., Kishmoto, Y., Kolodny, E. and Suzuki, K. (1976) Fatty acid abnormality in adrenoleukodystrophy. J. Neurochem., 26, 851–860. source
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationA healthy membrane is important for axonal function.
“thus underscoring the importance of a healthy membrane for axonal function.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenCrucial experiments (locomotor tests and EMG) have been confirmed with pure C57BL/6J background mice.
“Crucial experiments (locomotor tests and EMG) have been confirmed with pure C57BL/6J background mice.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenResults described in this manuscript are derived from mice on a mixed C57BL/6J/129Sv background (87% C57BL/6J and 13%129Sv).
“Results described in this manuscript are derived from mice on a mixed C57BL/ 6J/129Sv background (87% C57BL/6J and 13%129Sv).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenHistology, morphometric, behavioral testing and electrophysiological experiments were performed in a blind way with respect to the animal's genotype.
“Histology, morphometric, behavioral testing and electrophysiological experiments were performed in a blind way with respect to the animal's genotype.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
No human disease has been attributed to defects in the genes coding for ALDRP (ABCD2), PMP70 (ABCD3) or PMP69 (ABCD4).
“To date, no human disease has been attributed to defects in the genes coding for ALDRP (ABCD2), PMP70 (ABCD3) or PMP69 (ABCD4).”
The paper relies on this without support.
The functions of ABCD2, ABCD3 and ABCD4 in higher eukaryotes are unknown.
“The functions of the three other transporters in higher eukaryotes are unknown”
The paper relies on this without support.
No human syndrome compatible with the abcd2-/- phenotype has been linked to the ABCD2 locus at 12q1.1-1.2.
“To date, no human syndrome compatible with this phenotype has been linked to the ABCD2 locus at 12q1.1 -1.2.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Electron microscopy in Abcd2 KO mice showed the first signs of spinal cord axonal pathology at 12 months, yet no histological abnormalities.
“Electron microscopy in Abcd2 KO mice showed the first signs of spinal cord axonal pathology at 12 months, yet no histological abnormalities.”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [196]
The Biochemical function of ALDRP section (page not supplied) says histological abnormalities in the spinal cord were not demonstrable at 12 months, while the first signs of pathology at that age were APP and synaptophysin accumulations in axonal swellings. It attributes those early findings to immunohistochemical analysis, not electron microscopy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn Abcd2-deficient mice, saturated VLCFA do not generally accumulate; increased C26:0 levels have been detected exclusively in the dorsal root ganglia of young Abcd2-deficient mice.
“In Abcd2-deficient mice, saturated VLCFA do not generally accumulate; increased C26∶0 levels have been detected exclusively in the dorsal root ganglia of young Abcd2-deficient mice [33].”
From Abcd2 Is a Strong Modifier of the Metabolic Impairments in Peritoneal Macrophages of Abcd1-Deficient Mice (2014) · cites this paper as [33]
Dorsal root ganglia are a notable exception to the lack of effect of Abcd2 inactivation on saturated VLCFA levels, which may explain the earlier onset of a sensory motor phenotype in Abcd1/Abcd2 double-deficient and Abcd2 single-deficient mice compared with Abcd1-deficient mice.
“One notable exception are the dorsal root ganglia [33], which may explain the earlier onset of a sensory motor phenotype in Abcd1/Abcd2 double-deficient and Abcd2 single-deficient mice compared with Abcd1-deficient mice [31].”
From Abcd2 Is a Strong Modifier of the Metabolic Impairments in Peritoneal Macrophages of Abcd1-Deficient Mice (2014) · cites this paper as [33]
At 12 months of age, Abcd2 KO mice already displayed a marked impairment in motor performance, which aggravated up to 20 months.
“At 12 months of age, Abcd2 KO mice already displayed a marked impairment in their motor performance, which aggravated up to 20 months.”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [196]
The brain of Abcd2 KO mice showed no significant difference compared to wild type littermates.
“The brain of Abcd2 KO mice showed no significant difference compared to wild type littermates.”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [196]
Histological abnormalities in spinal cord dorsal and ventral columns of Abcd2 KO mice became evident at 20 months, while atrophy or death of Purkinje cells was detected in the cerebellum.
“Histological abnormalities in spinal cord dorsal and ventral columns became evident at 20 months, while atrophy or death of Purkinje cells was detected in the cerebellum.”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [196]
Abcd1:Abcd2 double KO mice had an earlier onset of symptoms with more severe motor deficits, axonal degeneration, and myelin alterations, but no cerebral pathology.
“Abcd1: Abcd2 double KO mice had an earlier onset of symptoms with more severe motor deficits (at 20 months of age, 6 out of 11 mice were not able to perform motor tests), axonal degeneration, and myelin alterations, but no cerebral pathology.”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [196]
The more severe locomotor phenotype in Acbd2-/- mice is associated with degeneration of central motor centers.
“Moreover, Acbd2–/– mice develop signs of ataxia corresponding to a significant decline in cerebellar Purkinje neurons at the age of 20 months, suggesting that the more severe locomotor phenotype is associated with the degeneration of central motor centers (Ferrer et al., 2005).”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Ferrer et al., 2005
Acbd2-/- mice develop signs of ataxia corresponding to a significant decline in cerebellar Purkinje neurons at the age of 20 months.
“Moreover, Acbd2–/– mice develop signs of ataxia corresponding to a significant decline in cerebellar Purkinje neurons at the age of 20 months, suggesting that the more severe locomotor phenotype is associated with the degeneration of central motor centers (Ferrer et al., 2005).”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Ferrer et al., 2005
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Fibroblast β-oxidation cites the wrong Figure 3 panel
MinorThe results cite Figure 3G and H for the fibroblast β-oxidation finding, whereas the caption places that measurement in panel F; panels G and H show fatty-acid levels.
“In this cell type, lack of ALDRP is neither translated into an accumulation of VLCFAs nor into a decrease of C26:0 b-oxidation capacity (Fig. 3G and H).”
“(F) Capacity of adult fibroblasts to b-oxidize C26:0, expressed as picomoles per hour per milligram of protein.”
Purkinje neurofilament result cites GFAP panels
MinorThe results point to Figure 7E and F for reduced neurofilament staining, but the caption assigns that finding to panel H and identifies panel F as GFAP staining.
“A clear reduction of non-phosphorylated neurofilaments in Purkinje cells (SMI 32 antibody) (23) indicated reduced dendritic arborization (Fig. 7E and F).”
“(F) Focal upregulations of GFAP expression in aldr2/2.(H) Strong reduction of non-phosphorylated neurofilaments in Purkinje cells was seen by staining with anti-SMI32.”
DRG measurements cite nonexistent Figure 3 panels
MinorThe text assigns the DRG C26:0 result to Figure 3I and J, but the figure caption identifies the fatty-acid measurements as panels G and H and lists no panels I or J.
“We could indeed detect an accumulation of C26:0 in DRGs from abcd22/2 mice (Fig. 3I and J, P , 0.002).”
“(G and H) Quantification of saturated VLCFA levels by ESI-MS in adult fibroblasts and DRG samples, expressed as micromoles per milligram of protein.”
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Sorted by citations
The Peroxisome-Mitochondria Connection: How and Why?
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BackgroundSelf-citationGeneral aspects and neuropathology of X-linked adrenoleukodystrophy
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“Altered mitochondria have also been observed in neurons of spinal cords of ABCD1 and ABCD2- mice (41).”
BackgroundSelf-citationAntioxidants halt axonal degeneration in a mouse model of X‐adrenoleukodystrophy
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“Also, locomotor testing is facilitated in this model, as the first signs of neurological involvement can be seen at 15 months of age, using the bar cross test.(38) For the sake of starting the treatment on symptomatic mice, we re-evaluated locomotor skills by using the bar cross(38) and treadmill tests,(39) starting a…”
BackgroundMethodInfluentialSelf-citationMitochondria and peroxisomes: Are the ‘Big Brother’ and the ‘Little Sister’ closer than assumed?
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“Of note, we and others have previously described ultrastructural abnormalities in mitochondria from neurons of Abcd1(2) and Abcd2 mouse spinal cords (22) and Abcd1(2) adrenocortical cells (23), consistent with observations in AMN patients (24,25), and peroxisomal-deficient Zellweger patients (26) and Pex5 mice (27).”
ResultSelf-citationABC lipid transporters: Extruders, flippases, or flopless activators?
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“An Abcd2 knockout mouse model has been generated and characterized (Ferrer et al., 2005).”
BackgroundMethodSelf-citationThe peroxisomal ABC transporter family
Wanders, R. J. A., Visser, W. F., van Roermund, C. W. T., Kemp, S., & Waterham, H. R. (2006) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-006-0142-x · Cited by 111 · see citing works
“Furthermore, mitochondrial, Golgi, and endoplasmic reticulum abnormalities were observed, indicative of a disturbed organellar network, which may be at the origin of the pathological cascade [19].”
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Self-citationA key role for the peroxisomal<i>ABCD2</i>transporter in fatty acid homeostasis
Fourcade, S., Ruiz, M., Camps, C., Schlüter, A., Houten, S. M., Mooyer, P. A. W., Pàmpols, T., Dacremont, G., Wanders, R. J. A., Giròs, M., et al. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90736.2008 · Cited by 104 · see citing works
Self-citationN-acetylcysteine Pharmacology and Applications in Rare Diseases—Repurposing an Old Antioxidant
Sahasrabudhe, S. A., Terluk, M. R., & Kartha, R. V. (2023) · Antioxidants · doi:10.3390/antiox12071316 · Cited by 102 · see citing works
Pastural, É., Ritchie, S. A., Lu, Y., Jin, W., Kavianpour, A., Su-Myat, K. K., Heath, D., Wood, P. L., Fisk, M., & Goodenowe, D. B. (2009) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2009.06.003 · Cited by 100 · see citing works
Organelle dynamics and dysfunction: A closer link between peroxisomes and mitochondria
Camões, F., Bonekamp, N. A., Delille, H. K., & Schrader, M. (2008) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-008-1018-3 · Cited by 91 · see citing works
“…2004; Epstein et al 2001; Motley et al 2008), and ultrastructural and functional mitochondrial alterations were observed under conditions in which peroxisome biogenesis or function was impaired (Baumgart et al 2001; Dirkx et al 2005; Fan et al 1998; Ferrer et al 2005; McGuinness et al 2003).”
BackgroundCurrent and Future Pharmacological Treatment Strategies in X‐Linked Adrenoleukodystrophy
Berger, J., Pujol, A., Aubourg, P. R., & Forss‐Petter, S. (2010) · Brain Pathology · doi:10.1111/j.1750-3639.2010.00393.x · Cited by 90 · see citing works
“Mice with targeted inactivation of both Abcd1 and Abcd2 develop late-onset AMN-like myelopathy and axonal degeneration in the spinal cord, months before axonopathy and motor behavior-deficits are detected in Abcd1 single mutant mice (24, 84, 85) and were selected for this trial in order to allow evaluation of long-ter…”
BackgroundSelf-citationGlutathione and peroxisome redox homeostasis
Ferreira, M. J., Rodrigues, T. A., Pedrosa, A. G., Silva, A. R., Vilarinho, B. G., Francisco, T., & Azevedo, J. E. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102917 · Cited by 94 · see citing works
The ins and outs of peroxisomes: Co-ordination of membrane transport and peroxisomal metabolism
Rottensteiner, H., & Theodoulou, F. L. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.08.012 · Cited by 84 · see citing works
Galino, J., Ruíz, M., Fourcade, S., Schlüter, A., López‐Erauskin, J., Guilera, C., Jové, M., Naudí, A., García‐Arumí, E., Andreu, A. L., et al. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3877 · Cited by 85 · see citing works
“Evidence of ultrastructural anomalies of mitochondria in spinal neurons of Abcd1 - mice have been reported (18); this is consistent with previous findings of mitochondria alterations in liver of peroxisomal deficient models (5).”
Self-citationAbnormal Muscle Spindle Innervation and Large-Fiber Neuropathy in Diabetic Mice
Muller, K. A., Ryals, J. M., Feldman, E. L., & Wright, D. E. (2008) · Diabetes · doi:10.2337/db08-0022 · Cited by 82 · see citing works
Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy
Morató, L., Galino, J., Ruíz, M., Calingasan, N. Y., Starkov, A. A., Dumont, M., Naudí, A., Martínez, J. J., Aubourg, P. R., Portero‐Otín, M., et al. (2013) · Brain · doi:10.1093/brain/awt143 · Cited by 82 · see citing works
“Spinal cords were harvested from 12-month-old wild-type and Abcd1 / or 18-month-old wild-type, Abcd1 / /Abcd2 / and Abcd1 / /Abcd2 / mice fed with pioglitazone for 4 months, after perfusion with 4% paraformaldehyde, as described (Pujol et al., 2004; Ferrer et al., 2005; Lopez-Erauskin et al., 2011).”
Self-citationPena, S. D. J., & Coimbra, R. (2014) · Clinical Genetics · doi:10.1111/cge.12542 · Cited by 76 · see citing works
“The ABCD2 variant had some pathogenic features, but the phenotype was of a late-onset ataxia in mice (1), rather than the infantile onset we saw in our patient.”
BackgroundFourcade, S., Ferrer, I., & Pujol, A. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.05.041 · Cited by 77 · see citing works
Self-citationSingh, J., Khan, M., & Singh, I. (2008) · Journal of Lipid Research · doi:10.1194/jlr.m800321-jlr200 · Cited by 75 · see citing works
Organelle interplay in peroxisomal disorders
Thoms, S., Grønborg, S. W., & Gärtner, J. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.05.002 · Cited by 74 · see citing works
Functional genomic analysis unravels a metabolic-inflammatory interplay in adrenoleukodystrophy
Schlüter, A., Espinosa, L., Fourcade, S., Galino, J., López, E., Ilieva, E., Morató, L., Asheuer, M., Cook, T., McLaren, A., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/ddr536 · Cited by 72 · see citing works
“The generation and genotyping of Abcd1 mice have been previously described (8,9,11,51).”
MethodSelf-citationPeroxisomal ABC Transporters: An Update
Tawbeh, A., Gondcaille, C., Trompier, D., & Savary, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22116093 · Cited by 68 · see citing works
Jorge-Torres, O. C., Szczęsna, K., Roa, L., Casal, C., Somermeyer, L. G., Soler, M., Velasco, C. D., Segundo, P. M. S., Petazzi, P., Sáez, M., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.04.010 · Cited by 65 · see citing works
“The test was carried out as described previously (Ferrer et al., 2005).”
MethodSelf-citationPeroxisomes, myelination, and axonal integrity in the CNS
Baes, M., & Aubourg, P. (2009) · The Neuroscientist · doi:10.1177/1073858409336297 · Cited by 65 · see citing works
Launay, N., Ruíz, M., Grau, L., Ortega, F. J., Ilieva, E. V., Martínez, J. J., Galea, E., Ferrer, I., Knecht, E., Pujol, A., et al. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1655-9 · Cited by 63 · see citing works
“Morphological abnormalities of the ER compartment have been described in peroxisomal mutants, including Pex5−/− [18] and Abcd2−/− mice [27].”
BackgroundSelf-citationFourcade, S., López-Erauskin, J., Ruiz, M., Ferrer, I., & Pujol, A. (2014) · Biochimie · doi:10.1016/j.biochi.2013.09.012 · Cited by 55 · see citing works
Self-citationVerheijden, S., Bottelbergs, A., Krysko, O., Krysko, D. V., Beckers, L., De Munter, S., Van Veldhoven, P. P., Wyns, S., Kulik, W., Nave, K.-A., et al. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.06.006 · Cited by 54 · see citing works
“Interestingly, a late onset mild ataxia (from 15 months) with loss of Purkinje cells (from 20 months) was observed in both Abcd1 and Abcd2 knockoutmice (Ferrer et al., 2005).”
BackgroundGenin, E. C., Geillon, F., Gondcaille, C., Athias, A., Gambert, P., Trompier, D., & Savary, S. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.211912 · Cited by 53 · see citing works
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Autophagy induction halts axonal degeneration in a mouse model of X-adrenoleukodystrophy
Launay, N., Aguado, C., Fourcade, S., Ruíz, M., Grau, L., Riera, J., Guilera, C., Girós, M., Ferrer, I., Knecht, E., et al. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1378-8 · Cited by 51 · see citing works
“onset at 12 months of age [16, 64, 65]; therefore, this is”
BackgroundMethodInfluentialSelf-citationSteroid Hormones Control Circadian Elovl3 Expression in Mouse Liver
Brolinson, A., Fourcade, S., Jakobsson, A., Pujol, A., & Jacobsson, A. (2008) · Endocrinology · doi:10.1210/en.2007-1402 · Cited by 51 · see citing works
Self-citationLu, J., Barron‐Casella, E. A., Brose, R. D., Heinzer, A. K., Moser, A. B., Bentley, K. L. D. M., Wand, G. S., McGuinness, M. C., Pei, Z., Watkins, P. A., et al. (2007) · Laboratory Investigation · doi:10.1038/labinvest.3700512 · Cited by 48 · see citing works
“Its physiological function is also unknown; even though no known human disease is associated with this gene, overexpression of abcd2/ABCD2 can compensate for the loss of abcd1/ABCD1 in the mouse in vivo and in cultured human and mouse fibroblasts.5,6 There is overlap of ABCD1 and ABCD2 expression in several tissues, b…”
BackgroundSelf-citationYamanishi, K., Maeda, S., Kuwahara‐Otani, S., Watanabe, Y., Yoshida, M., Ikubo, K., Okuzaki, D., El‐Darawish, Y., Li, W., Nakasho, K., et al. (2016) · Translational research · doi:10.1016/j.trsl.2016.03.010 · Cited by 47 · see citing works
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Generalised and conditional inactivation of Pex genes in mice
Baes, M. I., & Veldhoven, P. P. V. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.08.018 · Cited by 45 · see citing works
Peroxisomal Disorders: A Review on Cerebellar Pathologies
Munter, S. D., Verheijden, S., Régal, L., & Baes, M. I. (2015) · Brain Pathology · doi:10.1111/bpa.12290 · Cited by 44 · see citing works
“However, PC death was reported in the cerebellum of aged ABCD1-deficient mice (45), corresponding with the rare X-ALD patients with primary cerebellar atrophy.”
BackgroundMuneer, Z., Wiesinger, C., Voigtländer, T., Werner, H. B., Berger, J., & Forss-Petter, S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0108655 · Cited by 33 · see citing works
“In Abcd2-deficient mice, saturated VLCFA do not generally accumulate; increased C26:0 levels have been detected exclusively in the dorsal root ganglia of young Abcd2-deficient mice [33].”
BackgroundFunctional Characterization of IPSC-Derived Brain Cells as a Model for X-Linked Adrenoleukodystrophy
Baarine, M., Khan, M., Singh, A., & Singh, I. (2015) · PLOS ONE · doi:10.1371/journal.pone.0143238 · Cited by 38 · see citing works
Rodríguez-Pascau, L., Vilalta, A., Cerrada, M., Traver, E., Forss-Petter, S., Weinhofer, I., Bauer, J., Kemp, S., Pina, G., Pascual, S., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abc0555 · Cited by 40 · see citing works
Self-citationSingh, J., Khan, M., & Singh, I. (2011) · Journal of Lipid Research · doi:10.1194/jlr.m017491 · Cited by 37 · see citing works
Liu, J., Sabeva, N. S., Bhatnagar, S., Li, X., Pujol, A., & Graf, G. A. (2009) · Journal of Lipid Research · doi:10.1194/jlr.m900237-jlr200 · Cited by 36 · see citing works
Self-citationActivation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy
Morató, L., Ruíz, M., Boada, J., Calingasan, N. Y., Galino, J., Guilera, C., Jové, M., Naudí, A., Ferrer, I., Pamplona, R., et al. (2015) · Cell Death and Differentiation · doi:10.1038/cdd.2015.20 · Cited by 33 · see citing works
“The Abcd1/Abcd2 mice, compared with the Abcd1 mice, display greater VLCFA accumulation in the spinal cord,(19) higher levels of oxidative damage to proteins,(20) and a more severe AMN-like pathology with an earlier onset at 12 months of age.(19,67) It is worth mentioning that to date, no disease-causative role for ABC…”
Self-citationDarwisch, W., von Spangenberg, M., Lehmann, J., Singin, Ö., Deubert, G., Kühl, S., Roos, J., Horstmann, H., Körber, C., Hoppe, S., et al. (2020) · Communications Biology · doi:10.1038/s42003-020-01442-x · Cited by 32 · see citing works
Singh, I., Samuvel, D. J., Choi, S., Saxena, N., Singh, A. K., & Won, J. (2018) · Immunology · doi:10.1111/imm.12893 · Cited by 29 · see citing works
Szczęsna, K., Jorge-Torres, O. C., Petazzi, P., Soler, M., Roa, L., Sáez, M., Fourcade, S., Pujol, A., Artuch-Iriberri, R., Molero-Luís, M., et al. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.136 · Cited by 28 · see citing works
“The bar cross test, as previously described (Ferrer et al, 2005; Lopez-Erauskin et al, 2011), was also carried out.”
BackgroundMethodSelf-citationFourcade, S., Goicoechea, L., Parameswaran, J., Schlüter, A., Launay, N., Ruíz, M., Seyer, A., Colsch, B., Calingasan, N. Y., Ferrer, I., et al. (2020) · Brain Pathology · doi:10.1111/bpa.12869 · Cited by 27 · see citing works
“Compared with the Abcd1- mice, the Abcd1−/Abcd2−/− mice display enhanced VLCFA accumulation in the spinal cord (57), higher levels of oxidative damage to proteins (21), and a more severe AMN-like pathology with an earlier onset at 12 months of age (16,57,58); therefore, this is the preferred model for assaying therape…”
BackgroundMethodInfluentialSelf-citationMastroeni, R., Bensadoun, J., Charvin, D., Aebischer, P., Pujol, A., & Raoul, C. (2009) · Annals of Neurology · doi:10.1002/ana.21677 · Cited by 27 · see citing works
“Interestingly, Abcd1 / ; Abcd2 / mice develop late-onset myelopathy with axonal degeneration that resembles adrenomyeloneuropathy.(4,5) Studies in humans and mice demonstrated that myelin and oligodendrocytes are the primary targets of the disease, with axonal degeneration being regarded as a consequence of the loss o…”
BackgroundMethodSelf-citationRen, Y., Diao, F., Katari, S., et al. (2018) · Molecular Genetics & Genomic Medicine · doi:10.1002/mgg3.345 · Cited by 26 · see citing works
“ABCD2 was ruled out as a candidate because mouse knockouts had cerebellar and sensory ataxia without infertility (Ferrer et al., 2005).”
BackgroundThe Fast and the Furious: Golgi Contact Sites
David, Y., Castro, I. G., & Schuldiner, M. (2021) · Contact · doi:10.1177/25152564211034424 · Cited by 24 · see citing works
“Deletion of ABCD2 in mice caused accumulation of VLCFAs and disruption of the Golgi architecture which resulted in neurodegeneration (Ferrer et al., 2005).”
BackgroundSingh, J., Khan, M., Pujol, A., Baarine, M., & Singh, I. (2013) · PLoS ONE · doi:10.1371/journal.pone.0070712 · Cited by 24 · see citing works
“Moreover, Abcd2/Aldrp shares a high degree of overlapping biochemical functions regarding the catabolism of VLCFA in vivo [39,40].”
BackgroundSelf-citationThe absence of ABCD2 sensitizes mice to disruptions in lipid metabolism by dietary erucic acid
Liu, J., Liang, S., Liu, X., Brown, J. A., Newman, K. E., Sunkara, M., Morris, A. J., Bhatnagar, S., Li, X., Pujol, A., et al. (2012) · Journal of Lipid Research · doi:10.1194/jlr.m022160 · Cited by 23 · see citing works
Self-citationSingh, J., Khan, M., & Singh, I. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2013.01.004 · Cited by 21 · see citing works
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Advances and Pitfalls of Cell Therapy in Metabolic Leukodystrophies
Miranda, C. O., Brites, P., Sousa, M. M., & Teixeira, C. A. (2013) · Cell Transplantation · doi:10.3727/096368912x656117 · Cited by 19 · see citing works
Clinical and Neuroimaging Spectrum of Peroxisomal Disorders
Tan, A. P., Gonçalves, F. G., Almehdar, A., & Soares, B. P. (2018) · Topics in Magnetic Resonance Imaging · doi:10.1097/rmr.0000000000000172 · Cited by 16 · see citing works
Trompier, D., & Savary, S. (2013) · Colloquium Series on The Genetic Basis of Human Disease · doi:10.4199/c00075ed1v01y201303gbd004 · Cited by 16 · see citing works
In vivo labeling of peroxisomes by photoconvertible mEos2 in myelinating glia of mice
Richert, S., Kleinecke, S., Günther, J., Schaumburg, F., Edgar, J. M., Nienhaus, G. U., Nave, K., & Kassmann, C. M. (2013) · Biochimie · doi:10.1016/j.biochi.2013.10.022 · Cited by 16 · see citing works
Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy
Launay, N., Lopez-Erauskin, J., Bianchi, P., Guha, S., Parameswaran, J., Coppa, A., Torreni, L., Schlüter, A., Fourcade, S., Paredes-Fuentes, A. J., et al. (2024) · Brain · doi:10.1093/brain/awae038 · Cited by 14 · see citing works
Self-citationDemonstration of bile acid transport across the mammalian peroxisomal membrane
Visser, W. F., van Roermund, C. W. T., IJlst, L., Waterham, H. R., & Wanders, R. J. A. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.03.083 · Cited by 13 · see citing works
Self-citationFowler, J. C., Zecchini, V. R., & Jones, P. H. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020767 · Cited by 12 · see citing works
“Transcription of two genes involved in fatty acid uptake were up-regulated at 6 hours post-induction (Table 1); Abcd2, a gene known to be involved in the peroxisomal import of fatty acids [37], and the very low density lipoprotein receptor (Vldlr) [38].”
BackgroundLiver X receptors: A therapeutic target in demyelinating disorders
Richartz, J., Yam, S. C., Zhan, N., Schepers, M., Tiane, A., Mulder, M. T., Wens, I., & Vanmierlo, T. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107861 · Cited by 12 · see citing works
Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy
Bougnères, P., & Le Stunff, C. (2025) · Genes · doi:10.3390/genes16050590 · Cited by 11 · see citing works
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Ranea‐Robles, P., Galino, J., Espinosa, L., Schlüter, A., Ruíz, M., Calingasan, N. Y., Villarroya, F., Naudí, A., Pamplona, R., Ferrer, I., et al. (2021) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12747 · Cited by 10 · see citing works
Self-citationEnoyl thioester reductases—enzymes of fatty acid synthesis and degradation in mitochondria
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Liu, X., Liu, J., Liang, S., Schlüter, A., Fourcade, S., Aslibekyan, S. W., Pujol, A., & Graf, G. A. (2014) · Molecular Pharmacology · doi:10.1124/mol.114.092742 · Cited by 9 · see citing works
“505 cells and accumulation of VLCFA in dorsal root ganglia cells (Ferrer et al., 2005).”
BackgroundSelf-citationA novel cell model to study the function of the adrenoleukodystrophy-related protein
Gueugnon, F., Volodina, N., Taouil, J. E., Lopez, T. E., Gondcaille, C., Grand, A. S.-L., Mooijer, P. A. W., Kemp, S., Wanders, R. J. A., & Savary, S. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.12.152 · Cited by 9 · see citing works
Self-citationLipid Dyshomeostasis and Inherited Cerebellar Ataxia
Zhao, J., Zhang, H., Fan, X., Yu, X., & Huai, J. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02826-2 · Cited by 8 · see citing works
Parameswaran, J., Goicoechea, L., Planas‐Serra, L., Pastor, A., Ruíz, M., Calingasan, N. Y., Guilera, C., Aso, E., Boada, J., Pamplona, R., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02451-2 · Cited by 8 · see citing works
“Compared with the Abcd1− mice, DKO mice display greater VLCFA accumulation in the spinal cord [32, 68], higher levels of oxidative damage to proteins [31], and a more severe AMNlike pathology with an earlier onset at 12 months of age [28, 68], which makes this model better suited for preclinical therapeutic assays.”
BackgroundSelf-citationEmerging nanomaterials for targeting peroxisomes
Bachhuka, A., Yadav, T. C., Santos, A., Marsal, L. F., Ergün, S., & Karnati, S. (2022) · Materials Today Advances · doi:10.1016/j.mtadv.2022.100265 · Cited by 8 · see citing works
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The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models
Dawes, M. L., Haberlander, J. P., Islinger, M., & Schrader, M. (2025) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2025.1602343 · Cited by 7 · see citing works
Stem cells in genetic myelin disorders.
Kemp, K., Mallam, E., Scolding, N., & Wilkins, A. (2010) · Regenerative medicine · doi:10.2217/rme.10.10 · Cited by 9 · see citing works
Mouse Models to Study Peroxisomal Functions and Disorders: Overview, Caveats, and Recommendations
Kocherlakota, S., Swinkels, D., Veldhoven, P. P. V., & Baes, M. I. (2023) · Methods in molecular biology · doi:10.1007/978-1-0716-3048-8_34 · Cited by 5 · see citing works
Porcine arthrogryposis multiplex congenita (AMC): New diagnostic test and narrowed candidate region
Haubitz, M., Neuenschwander, S. M., & Vögeli, P. (2012) · Molecular and Cellular Probes · doi:10.1016/j.mcp.2012.02.005 · Cited by 5 · see citing works
Mouse Models of Metachromatic Leukodystrophy and Adrenoleukodystrophy
Aubourg, P. R., Sevin, C., & Cartier, N. (2010) · Neuromethods · doi:10.1007/978-1-60761-898-0_26 · Cited by 5 · see citing works
Single Peroxisomal Enzyme and Transporter Deficiencies in Human Diseases and Mouse Models
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Mouse Peroxisomal Protein cDNA Cloning and Characterization of its Intraclleular Localization
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Therapeutic Strategies for X-Linked Adrenoleukodystrophy, a Representative Peroxisomal Disorder
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Ultrastructural Pathology of Golgi Apparatus of Nerve Cells in Human Brain Edema
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Characterization & treatment of large sensory fiber peripheral neuropathy in diabetic mice
Muller, K. A. (2008) · KU ScholarWorks (University of Kansas) · Cited by 1 · see citing works
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Prediction of disease causing gene in Xq22.1 region of human X-chromosome
Niranjan, V., Ahmed, R., Seenivasagam, R., et al. (2011) · International Journal of Bioinformatics Research and Applications · doi:10.1504/ijbra.2011.040092
“Repeat masked genomic segments (Figure 1) were aligned with the chimp genome using BLAST and mouse (Ferrer et al., 2005), rat, fugu genomes using BLASTn (http://blast.”
MethodHaubitz, M. (2012) · Repository for Publications and Research Data (ETH Zurich) · doi:10.3929/ethz-a-007313540
“ABCD2 is associated with lateonset cerebellar and sensory ataxia (Pujol et al. 2005), while SLC2A13 has been shown to be involved in the control of the myo-inositol brain metabolism (Thorens et al.”
Ranea‐Robles, P. (2017) · Tesis Doctorals en Xarxa (Consorci de Serveis Universitaris de Catalunya)
Ferrer, I. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170609
Self-citation
- Authors
- Ferrer, I., Kapfhammer, J. P., Hindelang, C., Kemp, S., Troffer-Charlier, N., Broccoli, V., Callyzot, N., Mooyer, P., Selhorst, J., Vreken, P., Wanders, R. J. A., Mandel, J. L., & Pujol, A.
- Affiliations
- University of Basel (CH)
- Centre National de la Recherche Scientifique (FR)
- Amsterdam UMC Location University of Amsterdam (NL)
- Sig Holding (Switzerland) (CH)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-10-13
- Volume
- 14
- Issue
- 23
- Pages
- 3565-3577
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2099862428
- Cited by
- 106
- References
- 56
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 5 · 2022: 5 · 2021: 4 · 2020: 2 · 2019: 2 · 2018: 7 · 2017: 4 · 2016: 2 · 2015: 6 · 2014: 7 · 2013: 9 · 2012: 5
- FWCI
- 2.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- reroDoc Digital Library (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HAL (Le Centre pour la Communication Scientifique Directe) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- ABCD2, peroxisomal ABC transporters, late-onset ataxia, very long chain fatty acids, Purkinje cells, axonal degeneration, mitochondrial damage, endoplasmic reticulum damage
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Animals, Behavior, Animal, Cerebellum, Disease Models, Animal, Endoplasmic Reticulum, Golgi Apparatus, Mitochondria, Spinal Cord
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-11.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
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