Functional characterization of the adrenoleukodystrophy protein (ALDP) and disease pathogenesis
Abstract
X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder characterized by abnormal accumulation of saturated very long chain fatty acids in tissues and body fluids with predominance in brain white matter and adrenal cortex. The clinical phenotype is highly variable ranging from the severe childhood cerebral form to asymptomatic persons. The responsible ALD gene encodes the adrenoleukodystrophy protein (ALDP), a peroxisomal integral membrane protein that is a member of the ATP-binding cassette (ABC) transporter protein family. The patient gene mutations are heterogeneously distributed over the functional domains of ALDP. The extreme variability in clinical phenotype, even within one affected family, indicates that besides the ALD gene mutations other factors strongly influence the clinical phenotype. To understand the cell biology and function of mammalian peroxisomal ABC transporters and to determine their role in the pathogenesis of X-ALD we developed a system for expressing functional ABC protein domains in fusion with the maltose binding protein. Wild type and mutant fusion proteins of the nucleotide-binding fold were overexpressed, purified, and characterized by photoaffinity labeling with 8-azido ATP or 8-azido GTP and a coupled ATP regenerating enzyme assay for ATPase activity. Our studies provide evidence that peroxisomal ABC transporters utilize ATP to become a functional transporter and that ALD gene mutations alter peroxisomal transport function. The established disease model will be used further to study the influence of possible disease modifier proteins on ALDP function.
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The pathogenic variant p.Ser606Leu affects ATP-binding capacity and results in deficient VLCFA beta-oxidation.
“Studies using experimental cell lines showed that the pathogenic variant affects ATP-binding capacity (Database Refs 194 and 244) [22,23], resulting in deficient VLCFA beta-oxidation (Database Ref 261) [24].”
From Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy (2022) · cites this paper as [22]
Cites
The metabolic and molecular bases of inherited disease
Chen, Y.-T. (2001) · Medical Entomology and Zoology · Cited by 6,928 · see citing works
ABC Transporters: From Microorganisms to Man
Higgins, C. F. (1992) · Annual Review of Cell Biology · doi:10.1146/annurev.cb.08.110192.000435 · Cited by 3,985 · see citing works
Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters
Mosser, J., Douar, A.-M., Sarde, C.-O., Kioschis, P., Feil, R., Moser, H., Poustka, A.-M., Mandel, J.-L., & Aubourg, P. (1993) · Nature · doi:10.1038/361726a0 · Cited by 1,202 · see citing works
Moser, H. W., Mahmood, A., & Raymond, G. V. (2007) · Nature Clinical Practice Neurology · doi:10.1038/ncpneuro0421 · Cited by 663 · see citing works
Cutting, G. R., Kasch, L. M., Rosenstein, B. J., Zielenski, J., Tsui, L., Antonarakis, S. E., & Kazazian, H. H. (1990) · Nature · doi:10.1038/346366a0 · Cited by 397 · see citing works
Kemp, S., Pujol, A., Waterham, H. R., van Geel, B. M., Boehm, C. D., Raymond, G. V., Cutting, G. R., Wanders, R. J. A., & Moser, H. W. (2001) · Human Mutation · doi:10.1002/humu.1227 · Cited by 332 · see citing works
Hettema, E. H., van Roermund, C. W., Distel, B., van den Berg, M., Vilela, C., Rodrigues‐Pousada, C., Wanders, R. J., & Tabak, H. F. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00755.x · Cited by 323 · see citing works
[11] Coupled assay of Na+,K+-ATPase activity
Nørby, J. G. (1988) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(88)56014-7 · Cited by 322 · see citing works
Adrenoleukodystrophy: Phenotypic variability and implications for therapy
Moser, H. W., Moser, A. B., Smith, K. D., Bergin, A., Borel, J., Shankroff, J., Stine, O. C., Merette, C., Ott, J., Krivit, W., et al. (1992) · Journal of Inherited Metabolic Disease · doi:10.1007/bf01799621 · Cited by 239 · see citing works
The life cycle of the peroxisome
Titorenko, V. I., & Rachubinski, R. A. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35073063 · Cited by 213 · see citing works
Homo- and Heterodimerization of Peroxisomal ATP-binding Cassette Half-transporters
Liu, L. X., Janvier, K., Berteaux-Lecellier, V., Cartier, N., Benarous, R., & Aubourg, P. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.46.32738 · Cited by 141 · see citing works
The peroxisome biogenesis disorders
Gould, S. (2001) · Medical Entomology and Zoology · Cited by 127 · see citing works
Berger, J., Molzer, B., Fae, I., & Bernheimer, H. (1994) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1994.2855 · Cited by 126 · see citing works
McGuinness, M. C., Powers, J. M., Bias, W. B., Schmeckpeper, B. J., Segal, A. H., Gowda, V. C., Wesselingh, S. L., Berger, J., Griffin, D. E., & Smith, K. D. (1997) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(97)00020-9 · Cited by 89 · see citing works
Characterization and Analysis of Conserved Motifs in a Peroxisomal ATP-binding Cassette Transporter
Shani, N., Sapag, A., & Valle, D. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.15.8725 · Cited by 61 · see citing works
Gloeckner, C. J., Mayerhofer, P. U., Landgraf, P., Muntau, A. C., Holzinger, A., Gerber, J.-K., Kammerer, S., Adamski, J., & Roscher, A. A. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.2572 · Cited by 57 · see citing works
Clinical and Genetic Aspects of X-Linked Adrenoleukodystrophy
Gärtner, J., Braun, A. D., Holzinger, A., Roerig, P., Lenard, H. G., & Roscher, A. (1998) · Neuropediatrics · doi:10.1055/s-2007-973526 · Cited by 50 · see citing works
Self-citationSheps, J. A., Cheung, I. K., & Ling, V. W. T. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.24.14829 · Cited by 43 · see citing works
Roerig, P., Mayerhofer, P., Holzinger, A., & Gärtner, J. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)02235-9 · Cited by 40 · see citing works
Self-citation[56] Peroxisomal ABC transporters
Shani, N., & Valle, D. L. (1998) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(98)92058-4 · Cited by 35 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- Moser H. W., 2001, The Metabolic and Molecular Bases of Inherited Disease, 3257
- Roerig P., 2001, FEBS Lett., 24674, 1
Cited by
Sorted by citations
Progress in X-linked adrenoleukodystrophy
Moser, H. W., Dubey, P., & Fatemi, A. S. (2004) · Current Opinion in Neurology · doi:10.1097/00019052-200406000-00005 · Cited by 78 · see citing works
Mallack, E. J., Gao, K., Engelen, M., & Kemp, S. (2022) · Cells · doi:10.3390/cells11020283 · Cited by 60 · see citing works
“Studies using experimental cell lines showed that the pathogenic variant affects ATP-binding capacity (Database Refs 194 and 244) [22,23], resulting in deficient VLCFA beta-oxidation (Database Ref 261) [24].”
BackgroundLysosomal and Peroxisomal Disorders
Thomas, P. K., & Goebel, H. H. (2005) · Elsevier eBooks · doi:10.1016/b978-0-7216-9491-7.50082-x · Cited by 34 · see citing works
Xiong, C., Jia, L.-N., Xiong, W.-X., Wu, X., Xiong, L., Wang, T., Zhou, D., Hong, Z., Liu, Z., & Tang, L. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01280-9 · Cited by 19 · see citing works
Montagna, G., Biase, A. D., Cappa, M., Melone, M. A. B., Piantadosi, C., Colabianchi, D., Patrono, C., Attorri, L., Cannelli, N., Cotrufo, R., et al. (2005) · Human Mutation · doi:10.1002/humu.9303 · Cited by 12 · see citing works
“It has been speculated that some instances, if any, of genotype-phenotype correlation might require evaluation of residual ALDP expression (Gartner et al., 2002).”
BackgroundRetractedAdrenal steroids in adrenomyeloneuropathy
Wichers, M., Grigull, A., Sokolowski, P., Stoffel‐Wagner, B., & Köhler, W. (2005) · Journal of Neurology · doi:10.1007/s00415-005-0908-7 · Cited by 7 · see citing works
“Missense mutations in the ATP-binding fold cause AT-Pase dysfunction and ALD gene mutations alter peroxisomal transport function and may cause X-ALD [ 16 ].”
BackgroundGenetic and Metabolic Disorders of the White Matter
Vanderver, A. L., & Wolf, N. I. (2012) · Elsevier eBooks · doi:10.1016/b978-1-4377-0435-8.00071-8 · Cited by 6 · see citing works
Lo, M., Tsao, M., Hedley, D. W., et al. (2008) · Pancreas · doi:10.1097/mpa.0b013e318184aa8a · Cited by 4 · see citing works
“Adrenoleukodystrophy protein is mutated in ALD, a condition characterized by the inability to process long-chain fatty acids in the brain, thus adversely affecting the growth and development of myelin.(30,31) Although we observed AldP induction in response to K-ras activation and hypoxic treatment in transformed pancr…”
BackgroundGenetic and Metabolic Disorders of the White Matter
Vanderver, A. L., & Wolf, N. I. (2017) · Elsevier eBooks · doi:10.1016/b978-0-323-37101-8.00099-0 · Cited by 4 · see citing works
Gender issues in multiple sclerosis
McCombe, P. (2003) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.3.5.649 · Cited by 2 · see citing works
Adrenoleukodystrophy: Molecular, Metabolic, Pathologic, and Therapeutic Aspects
Contreras, M. A., & Singh, I. (2008) · Springer eBooks · doi:10.1007/978-0-387-30375-8_2 · Cited by 2 · see citing works
Identification of two de novo mutations in Chinese patients with X-linked adrenoleukodystrophy
Wang, Z., Ke, L., Yan, A.-Z., Zhu, Z., & Lan, F. (2008) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2008.331 · Cited by 1 · see citing works
“Defect in the ABCD1 gene impairs the peroxisomal capacity to metabolize very long chain saturated fatty acids (VLCFAs) via boxidation, leading to accumulation of VLCFAs in all parts of the body, including the brain and adrenal glands (3).”
BackgroundPre-symptomatic molecular diagnosis of X-linked adrenoleukodystrophy in Chinese families
Wang, Z., Ke, L., Xie, H., Yan, A.-Z., Huang, L., & Lan, F. (2009) · Neurological Research · doi:10.1179/016164109x12445616596364 · Cited by 1 · see citing works
ATP and Substrate Binding Regulates Conformational Changes of Human Peroxisomal ABC Transporter ALDPPreprint
Xiong, C., Jia, L.-N., Shen, M.-H., Xiong, W.-X., Xiong, L., Wang, T., Zhou, D., Liu, Z., & Tang, L. H. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.10.14.464310 · Cited by 1 · see citing works
“A large number of cases have been reported at the S606 and G512 position from signature motif and the Walker A motif respectively (Gartner et al., 2002; Kumar et al., 2011; Zhang et al., 2011), which interacts with the ATP molecule at the outward facing conformation.”
BackgroundATP and Substrate Binding Regulates Conformational Changes of Human Peroxisomal ABC Transporter ALDPPreprint
Tang, L., Xiong, C., Jia, L., Shen, M.-H., Xiong, W.-X., Xiong, L., Wang, T., Zhou, D., & Liu, Z. (2021) · Research Square · doi:10.21203/rs.3.rs-1002426/v1
- Authors
- Gärtner, J., Dehmel, T., Klusmann, A., & Roerig, P.
- Affiliations
- Heinrich Heine University Düsseldorf (DE)
- ORCID
- Gärtner, J.
- Venue
- Endocrine Research
- Publisher
- Informa UK Limited
- Published
- 2002-01
- Volume
- 28
- Issue
- 4
- Pages
- 741-748
- ISSN
- 0743-5800 (ISSN-L)
- 1532-4206
- OpenAlex
- W1986966017
- Semantic Scholar
- 14322764b3a5d9509d5ba022626cff54078032aa
- Cited by
- 15
- References
- 20
- Citations by year
- 2023: 1 · 2022: 1 · 2021: 2 · 2017: 1 · 2012: 1
- FWCI
- 1.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrine Research (publishedVersion)
- PubMed (publishedVersion)
- GRO (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- X-linked adrenoleukodystrophy, ALDP, ABC transporters, peroxisomes, very long chain fatty acids, ATPase activity, nucleotide binding fold, pathogenesis, genotype-phenotype variability, disease modifiers, photoaffinity labeling
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Member 1, Adenosine Triphosphate, Adrenoleukodystrophy, Humans, Genetic Linkage, Mutation, Phenotype, Protein Folding, ATP-Binding Cassette Transporters, Peroxisomes, Chromosomes, Human, X
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