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Cited by 201Metabolism and Genetic DisordersLysosomal Storage Disorders ResearchHereditary Neurological Disorders

Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy

Pujol, Aurora, Ferrer, Isidre, Camps, Carme, Metzger, Elisabeth, Hindelang, Colette, Callizot, Noëlle, Ruiz, Montse, Pàmpols, Teresa +2 more·2004·Human Molecular Genetics
DOI 10.1093/hmg/ddh323
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Abstract

X-linked adrenoleukodystrophy (X-ALD) is a severe neurodegenerative disease caused by loss of function of the peroxisomal transporter ABCD1 (ALD), which results in accumulation of very long chain fatty acids (VLCFAs) in organs and serum, central demyelination and peripheral axonopathy and Addison's disease. Knockout of the ALD gene in the mouse (ALD(-)) results in an adrenomyeloneuropathy-like disease (a late onset form of X-ALD). In the present study, we demonstrate that axonal damage occurs as first pathological event in this model, followed by myelin degeneration. We show that this phenotype can be modulated through expression levels of an ALD-related gene (ALDR/ABCD2), its closest paralogue and a target of PPARalpha and SREBP transcription factors. Overexpression of ALDR in ALD(-) mice prevents both VLCFAs accumulation and the neurodegenerative features, whereas double mutants for ALD and ALDR exhibit an earlier onset and more severe disease (including signs of inflammatory reaction) when compared with ALD single mutants. Thus, our results provide direct evidence for functional redundancy/overlap between both transporters in vivo and highlight ALDR as therapeutic target for treatment of X-ALD.

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Claims the paper makes

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  • Interpretationreasoning

    The absence of phenotype-genotype correlations in X-ALD suggests the existence of modifier genes, modifying environmental conditions and/or stochastic factors.

    “This striking absence of phenotype -genotype correlations suggests the existence of modifier genes, modifying environmental conditions and/or stochastic factors.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [13] Kemp, S., Pujol, A., Waterham, H.R., van Geel, B.M., Boehm, C.D., Raymond, G.V., Cutting, G.R., Wanders, R.J. and Moser, H.W. (2001) ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations. Hum. Mutat., 18, 499–515. source

      The GENOTYPEPHENOTYPE section reports a lack of correlation between ABCD1 mutations and disease severity, while the INTRODUCTION discusses proposed modifier genes and possible environmental factors. Neither passage proposes stochastic factors, so that part of the attributed explanation is unsupported by our copy; no page numbers are available. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [14] Moser, H., Smith, K.D., Watkins, P.A., Powers, J. and Moser, A.B. (2001) X-linked adrenoleukodystrophy. In Scriver, C. (ed.), The Metabolic and Molecular Bases of Inherited disease, 8th edn, McGraw-Hill, Vol. II, pp. 3303–3257.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Premisecitation

    Various forms of X-ALD may occur associated with the same mutation, even within the same family.

    “However, the various forms of the disease may occur associated to the same mutation, even within the same family (13,14).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [13] Kemp, S., Pujol, A., Waterham, H.R., van Geel, B.M., Boehm, C.D., Raymond, G.V., Cutting, G.R., Wanders, R.J. and Moser, H.W. (2001) ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations. Hum. Mutat., 18, 499–515. source
    • cites [14] Moser, H., Smith, K.D., Watkins, P.A., Powers, J. and Moser, A.B. (2001) X-linked adrenoleukodystrophy. In Scriver, C. (ed.), The Metabolic and Molecular Bases of Inherited disease, 8th edn, McGraw-Hill, Vol. II, pp. 3303–3257.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Premisecitation

    ABCD1 is implicated in the import of VLCFAs into the peroxisome.

    “it is proposed that ABCD1 is implicated in the import of VLCFAs into the peroxisome (19,20).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [19] Hettema, E.H., van Roermund, C.W., Distel, B., van den Berg, M., Vilela, C., Rodrigues-Pousada, C., Wanders, R.J. and Tabak, H.F. (1996) The ABC transporter proteins Pat1 and Pat2 are required for import of long-chain fatty acids into peroxisomes of Saccharomyces cerevisiae. EMBO J., 15, 3813–3822. source
    • cites [20] Shani, N., Watkins, P.A. and Valle, D. (1995) PXA1, a possible Saccharomyces cerevisiae ortholog of the human adrenoleukodystrophy gene. Proc. Natl Acad. Sci. USA, 92, 6012–6016. source
  • Premisecitation

    The only proven therapy available for X-ALD, at least for the CCALD phenotype, is bone marrow transplantation.

    “So far, the only proven therapy available for X-ALD, at least the CCALD phenotype, is bone marrow transplantation (45,46).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [45] Aubourg, P., Blanche, S., Jambaque, I., Rocchiccioli, F., Kalifa, G., Naud-Saudreau, C., Rolland, M.O., Debre, M., Chaussain, J.L., Griscelli, C. et al. (1990) Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. N. Engl. J. Med., 322, 1860–1866. source

      The paper reports improvement after bone marrow transplantation in one child with early cerebral disease, while the Discussion (p. 6) says this single case supports further evaluation. It does not establish transplantation as a proven therapy or the only available therapy; the Bone Marrow Transplantation section (p. 3) explicitly calls its benefits unproved. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [46] Shapiro, E., Krivit, W., Lockman, L., Jambaque, I., Peters, C., Cowan, M., Harris, R., Blanche, S., Bordigoni, P., Loes, D. et al. (2000) Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy. Lancet, 356, 713–718. source
  • Findingown data

    Overexpression of ALDR in ALD 2 mice prevents VLCFA accumulation.

    “Overexpression of ALDR in ALD 2 mice prevents both VLCFAs accumulation and the neurodegenerative features”
    Quote in the paperSubstantial claim
  • May combine two claims. 37
  • Classified as probably not a substantial claim. 11
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    Elevated levels of VLCFA have been shown to be detrimental to adrenocortical cells in culture and to model membranes.

    “although elevated levels of VLCFA have been shown to be detrimental to adrenocortical cells in culture (34,42) and to model membranes (43).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [34] Powers, J.M. (1985) Adreno-leukodystrophy (adreno-testiculo-leukomyelo-neuropathic-complex). Clin. Neuropathol., 4, 181–199.

      Not checked in the free run.

    • cites [42] Whitcomb, R.W., Linehan, W.M. and Knazek, R.A. (1988) Effects of long-chain, saturated fatty acids on membrane microviscosity and adrenocorticotropin responsiveness of human adrenocortical cells in vitro. J. Clin. Invest., 81, 185–188. source
    • cites [43] Ho, J.K., Moser, H., Kishimoto, Y. and Hamilton, J.A. (1995) Interactions of a very long chain fatty acid with model membranes and serum albumin. Implications for the pathogenesis of adrenoleukodystrophy. J. Clin. Invest., 96, 1455–1463. source

  • May combine two claims.

    Findingown data

    In the ALD 2 mouse model, axonal damage occurs as the first pathological event, followed by myelin degeneration.

    “In the present study, we demonstrate that axonal damage occurs as first pathological event in this model, followed by myelin degeneration.”
    • Also stated in: § Spinal cord histopathology. · plain
      “Thus, axonal degeneration precedes myelin disturbances in our mouse models, resembling findings in AMN patients (35).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At 20 months, ALD mutants exhibit slowing of both motor and sensitive conduction velocities.

    “At 20 months, ALD mutants exhibit slowing of both motor and sensitive conduction velocities.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ALDR 2/2 mice show a very similar type of spinal cord pathology to ALD 2 mice, and double mutant mice show it in a more severe manner.

    “A very similar type of pathology is found in ALDR 2/2 (Table 3), and in a more severe manner, in double mutant mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Spinal cord lesions in ALD 2 mice are ubiquitinated but do not colocalize with myelin lesions.

    “Those lesions are ubiquitinated (Fig. 2U -X), but they do not colocalize with myelin lesions as shown by serial sections analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At 22 months, ALD 2 mice present signs of microglia and astrocyte activation, numerous lectin-positive cells with morphological characteristics of ramified microglia/macrophages, and GFAP-positive cells in the spinal cord.

    “At 22 months, ALD 2 mice present signs of microglia and astrocyte activation, numerous lectin-positive cells with morphological characteristics of ramified microglia/macrophages, and glial fibrillary acidic protein (GFAP) positive cells (Fig. 2A -H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The C22:0 metabolite accumulates specifically in ALDR 2/2 adrenals and reaches a 4-fold increase in double mutants.

    “Interestingly, the C22:0 metabolite accumulated specifically in ALDR 2/2 adrenals and reached a 4-fold increase in double mutants.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    All mice described were born at expected Mendelian ratios and developed to maturity without showing abnormal clinical signs.

    “All mice described were born at expected Mendelian ratios and developed to maturity without showing any abnormal clinical signs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Absence of ALDR expression does not seem to influence electrophysiological parameters at 20 months; ALDR 2/2 mice show normal waves and double mutants do not have more important abnormalities than ALD 2 mice at this age.

    “The absence of ALDR expression does not seem to influence these parameters, since ALDR 2/2 mice show normal waves pattern, and double mutants do not have more important abnormalities than ALD 2 mice at this age.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In double mutants at 12 months, the latency of the motor wave and the SNCV are slowed down.

    “On the contrary, the latency of motor wave and the SNCV were slowed down in double mutants (Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    ALD 2 mice have intralysosomal needle-like cholesterol inclusions in the adrenal cortex, which are also seen in macrophages of ALD patients.

    “At the ultrastructural level, we observed in the ALD 2 mice (in particular in the fascicular cell layer of cortex and cortico-medullary junction), intralysosomal needle-like cholesterol inclusions, which are also seen in macrophages of ALD patients (34) (Fig. 1F).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Powers, J.M. (1985) Adreno-leukodystrophy (adreno-testiculo-leukomyelo-neuropathic-complex). Clin. Neuropathol., 4, 181–199.

  • May combine two claims.

    Findingown data

    In ALD 2/ALDR 2/2 mice, cholesterol inclusions are spread all over the cytoplasm and are encountered 10 times more often than in ALD 2 mice.

    “In ALD 2 / ALDR 2/2 mice, however, these inclusions were spread all over the cytoplasm, and are encountered 10 times more often than in ALD 2 mice (Fig. 1G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ALDR 2/2 animals are viable, fertile, and show no overt pathology or behavioural abnormalities until at least 6 months of age.

    “ALDR 2/2 animals were viable, fertile and showed no overt pathology or behavioural abnormalities until at least 6 months of age.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In double mutants, cholesterol needles are not restricted to lysosomes but are scattered all over the cytoplasm and are much more abundant.

    “(G) In double mutants, the cholesterol needles are not restricted to lysosomes, but are scattered all over the cytoplasm and are much more abundant.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 20 months of age, ALD 2 mice present an impairment of locomotor coordination in the rotarod test and exploratory abilities in the open field test.

    “At 20 months of age, ALD 2 mice presented an impairment of their locomotor coordination in the rotarod test (Fig. 3E) and exploratory abilities in the open field test (Fig. 3G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Double mutants exhibit the same range of VLCFA accumulation as ALD mutants (at least at 8 months of age) in spite of a more severe and earlier onset neurological phenotype.

    “Double mutants exhibit the same range of VLCFA accumulation than ALD mutants (at least at 8 months of age) in spite of a more severe and earlier onset neurological phenotype at the histological, behavioural and electrophysiological levels.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    APP and synaptophysin deposits are ubiquitinated.

    “APP and synaptophysin deposits are ubiquitinated (V, W).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    ALDR fully compensates for ALD loss upon overexpression, but its inactivation does not cause VLCFA accumulation in whole homogenates of CNS or PNS.

    “ALDR fully compensates for ALD loss upon overexpression, but its inactivation does not cause VLCFA accumulation in whole homogenates of CNS (brain and spinal cord) or PNS.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the open field, double mutants behave even less explorative than ALD 2 mice (P < 0.01) and have a marked tendency to freezing.

    “In the open field, double mutants behaved even less explorative than ALD 2 mice (P , 0.01), and had a marked tendency to freezing (long latency before starting the movement) (Fig. 3G).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    ALD mutant mice show fibrosis at the corticomedullary junction that is prevented by ALDR overexpression.

    “(C) ALD mutants show fibrosis at the corticomedular junction (arrows) that is prevented through ALDR overexpression in (D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In double knockouts, there is a synergistic accumulation of C22:0, C24:0 and C26:0, correlated with a very marked increase in numbers of speckles and cholesterol needles, together with a more dramatic accumulation of lipid droplets in virtually all adrenal cortex cell layers.

    “Consistently, in double knockouts we found a synergistic accumulation of C22:0, C24:0 and C26:0, which correlated with a very marked increase in numbers of speckles and cholesterol needles, together with a more dramatic accumulation of lipid droplets in virtually all adrenal cortex cell layers (fascicular, reticular and glomerular)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The inflammatory infiltrates are typically in small clusters (10-20 cells) adjacent to blood vessels and perimeningeal areas, and are composed mainly of T lymphocytes.

    “Those infiltrates were typically in small clusters (10 -20 cells) adjacent to blood vessels and perimeningeal areas, and were composed mainly of T lymphocytes (Fig. 3A -C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In adrenals, ALDR inactivation results in an increase of C22:0 (unlike ALD knockouts) and C24:0 fatty acids (similar levels to ALD 2 mice).

    “In contrast, in adrenals, ALDR inactivation results in an increase of C22:0 (unlike ALD knockouts) and C24:0 fatty acids (similar levels than in ALD 2 mice).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 20 months, ALD-/-/tgALDR mice have normal latency, CMAP amplitude, and SNCV compared to wild-type.

    “ALD (n ¼ 9) ALD 2 /tgALDR | 1.23 + 0.05 Ã 0.99 + 0.06 | 32.90 + 2.73 Ã 46.41 + 4.34 | 42.40 + 4.33 ÃÃ 53.60 + 3.14”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In ALD-/-/tgALDR mice, C26:0 levels and C26/C22 ratios are reduced compared to ALD-/- mice in spinal cord, sciatic nerve, and adrenal gland.

    “ALD 2/2 tg ALDR (n ¼ 5) | 8.01 + 1.35 | 9.71 + 1.03 | 0.39 + 0.12 Ãà | 0.05 + 0.02 ÃÔ
    • Also stated in: § Immunohistochemistry · plain
      “ALD 2 /tgALDR (n ¼ 2) | 15.96 + 2.40 † | 16.86 + 2.59 ÃÃ, ‡ | 0.11 + 0.01 ÃÃ, † ‡ | 0.01 + 0.00 ÃÔ
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 12 months, ALD-/-/ALDR-/- mice have increased latency and decreased SNCV compared to wild-type.

    “ALD 2 /ALDR 2/2 | 1.12 + 0.01 à | 42.18 + 11.23 | 44.53 + 6.55 ÃÔ
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In sciatic nerve at 8 months, ALD-/- mice have higher C26:0 levels and C26/C22 ratio than wild-type.

    “ALD 2 (n ¼ 5) | 11.92 + 1.83 | 28.72 + 3.57 | 3.80 + 0.57 à | 0.32 + 0.03 Ô
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In spinal cord at 8 months, ALD-/- mice have higher C26:0 levels and C26/C22 ratio than wild-type.

    “ALD 2 (n ¼ 8) ALDR 2/2 (n ¼ 4) | 7.54 + 1.78 6.93 + 1.40 7.92 + 1.25 | 10.38 + 1.65 11.22 + 2.56 7.62 + 0.97 | 0.37 + 0.07 2.46 + 0.66 Ã 0.69 + 0.23 | 0.05 + 0.01 0.36 + 0.05 Ã 0.09 + 0.04 |”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 20 months, ALD-/- mice have increased latency, decreased CMAP amplitude, and decreased SNCV compared to wild-type.

    “ALD (n ¼ 9) ALD 2 /tgALDR | 1.23 + 0.05 Ã 0.99 + 0.06 | 32.90 + 2.73 Ã 46.41 + 4.34 | 42.40 + 4.33 ÃÃ 53.60 + 3.14”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 20 months, ALD-/-/ALDR-/- mice have increased latency, decreased CMAP amplitude, and decreased SNCV compared to wild-type.

    “ALD 2 /ALDR 2/2 | 1.19 + 0.02 à | 33.85 + 6.02 à | 43.51 + 5.23 ÃÔ
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Loss of ABCD1 function results in accumulation of very long chain fatty acids (VLCFAs) in organs and serum, central demyelination, peripheral axonopathy, and Addison's disease.

    “which results in accumulation of very long chain fatty acids (VLCFAs) in organs and serum, central demyelination and peripheral axonopathy and Addison's disease.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Functional gene redundancy is a widespread mechanism in vertebrate evolution thought to increase robustness against deleterious mutations by backing up vital functions.

    “Functional gene redundancy is a widespread mechanism in vertebrate evolution, thought to increase robustness against deleterious mutations by 'backing-up' vital functions for the cell or the organism (1,2).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Thomas, J.H. (1993) Thinking about genetic redundancy. Trends Genet., 9, 395–399. source
    • cites [2] Gu, Z., Steinmetz, L.M., Gu, X., Scharfe, C., Davis, R.W. and Li, W.H. (2003) Role of duplicate genes in genetic robustness against null mutations. Nature, 421, 63–66. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    X-ALD patients accumulate VLCFA in plasma and tissues, notably in the adrenal cortex and nervous system.

    “X-ALD patients accumulate very long chain fatty acids (VLCFA) in plasma and tissues, notably in the adrenal cortex and nervous system.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Moser, H., Smith, K.D., Watkins, P.A., Powers, J. and Moser, A.B. (2001) X-linked adrenoleukodystrophy. In Scriver, C. (ed.), The Metabolic and Molecular Bases of Inherited disease, 8th edn, McGraw-Hill, Vol. II, pp. 3303–3257.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    ALDR/ABCD2 is the closest paralogue of ALD and a target of PPARa and SREBP transcription factors.

    “its closest paralogue and a target of PPARa and SREBP transcription factors.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [24] Berger, J., Albet, S., Bentejac, M., Netik, A., Holzinger, A., Roscher, A.A., Bugaut, M. and Forss-Petter, S. (1999) The four murine peroxisomal ABC-transporter genes differ in constitutive, inducible and developmental expression. Eur. J. Biochem., 265, 719–727. source
    • cites [25] Fourcade, S., Savary, S., Albet, S., Gauthe, D., Gondcaille, C., Pineau, T., Bellenger, J., Bentejac, M., Holzinger, A., Berger, J. et al. (2001) Fibrate induction of the adrenoleukodystrophy-related gene (ABCD2): promoter analysis and role of the peroxisome proliferator-activated receptor PPARalpha. Eur. J. Biochem., 268, 3490–3500. source
    • cites [28] Weinhofer, I., Forss-Petter, S., Zigman, M. and Berger, J. (2002) Cholesterol regulates ABCD2 expression: implications for the therapy of X-linked adrenoleukodystrophy. Hum. Mol. Genet., 11, 2701–2708. source

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisereasoning

    In a human genetic disease, a related gene whose function overlaps with the defective gene function may be considered as a therapeutic target.

    “In a human genetic disease, a related gene whose function overlaps with the defective gene function may be considered as therapeutic target.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Dietary treatment with 4PBA in ALD 2 mice partially corrects the accumulation of VLCFAs in brain and adrenal glands, correlating with ALDR protein induction and increased peroxisome proliferation.

    “Dietary treatment with 4PBA in ALD 2 mice has been shown to partially correct the accumulation of VLCFAs in brain and adrenal glands, correlating with ALDR protein induction and increased peroxisome proliferation (27).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Kemp, S., Wei, H.M., Lu, J.F., Braiterman, L.T., McGuinness, M.C., Moser, A.B., Watkins, P.A. and Smith, K.D. (1998) Gene redundancy and pharmacological gene therapy: implications for X-linked adrenoleukodystrophy. Nat. Med., 4, 1261–1268. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Histology, morphometry, behavioural testing and electrophysiological experiments were performed blind to the animal's genotype.

    “Histology, morphometry, behavioural testing and electrophysiological experiments were performed in a blind way with respect to the animal's genotype.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Infiltrating T lymphocytes (CD8þ) are often found in unaffected white matter of ALD and AMN/ALD patients, and also in acute demyelinative lesions together with macrophages.

    “Infiltrating T lymphocytes (CD8 þ ) are often found in unaffected white matter of ALD and AMN/ALD patients, and also in acute demyelinative lesions together with macrophages (44).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Ito, M., Blumberg, B.M., Mock, D.J., Goodman, A.D., Moser, A.B., Moser, H.W., Smith, K.D. and Powers, J.M. (2001) 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., 60, 1004–1019. source

  • May combine two claims.

    Interpretationreasoning

    Specificity of transported substrates is overlapping to some degree, but not identical between ALD and ALDR.

    “Alternatively and most likely, specificity of transported substrates is overlapping to some degree, but not identical between the two transporters.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Double knockouts may be useful to analyse the mechanisms of the inflammatory reaction that plays a major role in CCALD pathology in humans.

    “Thus, this suggests that double knockouts may be useful to analyse the mechanisms of the inflammatory reaction that plays a major role in CCALD pathology in humans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Axonal degeneration precedes myelin disturbances in the mouse models, resembling findings in AMN patients.

    “Thus, axonal degeneration precedes myelin disturbances in our mouse models, resembling findings in AMN patients (35).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Powers, J.M., DeCiero, D.P., Ito, M., Moser, A.B. and Moser, H.W. (2000) Adrenomyeloneuropathy: a neuropathologic review featuring its noninflammatory myelopathy. J. Neuropathol. Exp. Neurol., 59, 89–102. source

  • May combine two claims.

    Interpretationreasoning

    ALDR would be less efficient at substituting for ALD's function, and its overexpression would therefore be required to reach therapeutic benefit.

    “Thus, ALDR would be less efficient at substituting for ALD's function, and its overexpression would therefore be required to reach therapeutic benefit.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Plasma VLCFA levels in X-ALD patients are not related to phenotype onset or severity, nor does their normalization through a dietary treatment (Lorenzo's oil) seem to be curative or prevent disease onset.

    “Plasma VLCFA levels in patients are not related to phenotype onset or severity, nor does their normalization through a dietary treatment (Lorenzo's oil, a mixture of erucic and oleic acids) seems to be curative or prevents disease onset (14,41).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Moser, H., Smith, K.D., Watkins, P.A., Powers, J. and Moser, A.B. (2001) X-linked adrenoleukodystrophy. In Scriver, C. (ed.), The Metabolic and Molecular Bases of Inherited disease, 8th edn, McGraw-Hill, Vol. II, pp. 3303–3257.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [41] Aubourg, P., Adamsbaum, C., Lavallard-Rousseau, M.C., Rocchiccioli, F., Cartier, N., Jambaque, I., Jakobezak, C., Lemaitre, A., Boureau, F., Wolf, C. et al. (1993) A two-year trial of oleic and erucic acids (‘Lorenzo's oil’) as treatment for adrenomyeloneuropathy. N. Engl. J. Med., 329, 745–752. source

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    The endogenous ALDR gene is 5-10 times less expressed in physiological conditions than in the transgenic mice, and its normal expression pattern is not ubiquitous, being predominantly expressed in neurons in the CNS.

    “Many reasons can account for this fact, for instance that the endogenous ALDR gene is 5-10 times less expressed in physiological conditions than in the transgenic mice, and its normal expression pattern is not ubiquitous, being predominantly expressed in neurons in the CNS.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    Within the limits of potential interspecies differences, the findings warrant further efforts aiming at upregulation of ALDR as a therapy for X-ALD.

    “Altogether, and within the limits of potential interspecies differences, our findings warrant further efforts aiming at upregulation of ALDR as a therapy for X-ALD.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Findings in the ALD 2 mouse model and its modulation by ALDR can be extrapolated to human X-ALD patients.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    At least three sections corresponding to the dorsal columns of the spinal cord were analysed per animal and per stain.

    “At least three sections corresponding to the dorsal columns of the spinal cord were analysed per animal and per stain.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Crucial experiments (rotarod, open field tests and EMG) were confirmed with pure C57BL/6J background animals.

    “Crucial experiments (rotarod, open field tests and EMG) were confirmed with pure C57BL/6J background animals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The offspring of double heterozygous intercrosses obeyed Mendelian ratios.

    “Double heterozygous were intercrossed to obtain double knockout mice and wild-type littermate controls; the offspring obeyed mendelian ratios.”
    Quote in the paperNot a substantial claim
48 of 48

  • The paper relies on this without support.

    Findings in the ALD 2 mouse model and its modulation by ALDR can be extrapolated to human X-ALD patients.

    “Altogether, and within the limits of potential interspecies differences, our findings warrant further efforts aiming at upregulation of ALDR as a therapy for X-ALD.”
    “This fact suggests that precise tissue-specific upregulation may not be necessary for therapeutic benefit to patients.”
1 of 1

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?

  • Acbd2-/- mice did not develop symptoms.

    “Interestingly, Acbd1–/– mice, despite high VLCFA accumulation, do not develop cerebral disease and instead model the milder peripheral adrenomyelopathy, with late-onset symptoms appearing around 20 months of age, whereas Acbd2–/– mice did not develop symptoms (Pujol et al., 2004).”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Pujol et al., 2004

    The paper reports no overt pathology or behavioural abnormalities in ALDR (ABCD2)-deficient mice through at least six months, but that does not support an unqualified claim that they never developed symptoms. The Spinal cord histopathology section reports axonal pathology at 12 months and pathology similar to that of ALD-deficient mice at 22 months; page numbers are unavailable in our copy. (LLM, conf=0.86)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • 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 [31]

    Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • 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 [190]

    The Neurological phenotype passage reports earlier, more severe motor impairment in double mutants, and Spinal cord histopathology reports more severe axonal and myelin pathology (page numbers unavailable). The copy does not establish an absence of cerebral pathology or report that 6 of 11 mice could not perform motor tests at 20 months; the n=11 figure in Table 2 concerns nerve-conduction studies. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • 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 [190]

    The Spinal cord histopathology section reports abnormalities in ALDR−/− (Abcd2 knockout) mice, but it identifies an axonal marker at 12 months and describes further pathology at 22 months—not its first appearance at 20 months. The examined sections were of the dorsal spinal cord; our copy does not report ventral-column abnormalities or Purkinje-cell atrophy or death in the cerebellum. Page numbers were not available in the indexed passages. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • 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 [190]

    The Spinal cord histopathology section (page unavailable) reports the first marker of pathology at 12 months in Abcd2-knockout mice: synaptophysin-positive deposits in swollen axons. It identifies this finding through immunostaining, not electron microscopy, and the deposits are histopathological abnormalities; the claim’s assertion of no histological abnormalities is therefore unsupported. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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.

  • Conflicting ages for the adrenal histology in Figure 1

    Minor

    The results describe the ALD adrenal section shown in Figure 1C as coming from an 18-month-old mouse, but the figure caption dates the adrenal sections, including panel C, to 12 months.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Silva-Zolezzi, I., Hebron, K., Mihalik, S., Thomas, G., Valle, D. and Jimenez-Sanchez, G. (2003) Abcd3−/− mice have a non-shivering thermogenesis defect related to a disturbance in fasting fuel homeostasis. 53rd Annual Meeting of The American Society of Human Genetics. The American Society of Human Genetics, Los Angeles, California, Vol. 73, (suppl.) p. 199.

Cited by

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Related

Authors
Pujol, A., Ferrer, I., Camps, C., Metzger, E., Hindelang, C., Callizot, N., Ruiz, M., Pàmpols, T., Giròs, M., & Mandel, J. L.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Sig Holding (Switzerland) (CH)
Corresponding author
Pujol, Aurora
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2004-10-15
Volume
13
Issue
23
Pages
2997-3006
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddh323
OpenAlex
W2104564418
Cited by
201
References
48
Citations by year
2026: 2 · 2025: 5 · 2024: 10 · 2023: 9 · 2022: 11 · 2021: 7 · 2020: 11 · 2019: 7 · 2018: 6 · 2017: 10 · 2016: 6 · 2015: 8 · 2014: 12 · 2013: 14 · 2012: 10
FWCI
7.23
Type
journal article
Language
en
Open access
closed
Locations
  • Human Molecular Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • European Commission
  • Centre National de la Recherche Scientifique
  • Association Européenne contre les Leucodystrophies
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
X-linked adrenoleukodystrophy, ABCD1, ABCD2, very long chain fatty acids, functional redundancy, axonal injury, myelin degeneration, adrenomyeloneuropathy, PPARα, SREBP, therapeutic target, peroxisome biogenesis disorders
MeSH terms
ATP Binding Cassette Transporter, Subfamily D, ATP Binding Cassette Transporter, Subfamily D, Member 1, Adrenal Glands, Adrenoleukodystrophy, Animals, Humans, Mice, Mutant Strains, Mice, Transgenic, Microscopy, Electron, Phenotype, Spinal Cord, ATP-Binding Cassette Transporters, Mice

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.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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