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Cited by 32Metabolism and Genetic DisordersLipid metabolism and biosynthesisNeurological diseases and metabolism

Cerebellar and hepatic alterations in ACBD5-deficient mice are associated with unexpected, distinct alterations in cellular lipid homeostasis.

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Darwisch, Warda, von Spangenberg, Marino, Lehmann, Jana, Singin, Öznur, Deubert, Geralt, Kühl, Sandra, Roos, Johannes, Horstmann, Heinz +12 more·2020·Communications Biology
DOI 10.1038/s42003-020-01442-xPMC PMC7691522
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Abstract

ACBD5 deficiency is a novel peroxisome disorder with a largely uncharacterized pathology. ACBD5 was recently identified in a tethering complex mediating membrane contacts between peroxisomes and the endoplasmic reticulum (ER). An ACBD5-deficient mouse was analyzed to correlate ACBD5 tethering functions with the disease phenotype. ACBD5-deficient mice exhibit elevated very long-chain fatty acid levels and a progressive cerebellar pathology. Liver did not exhibit pathologic changes but increased peroxisome abundance and drastically reduced peroxisome-ER contacts. Lipidomics of liver and cerebellum revealed tissue-specific alterations in distinct lipid classes and subspecies. In line with the neurological pathology, unusual ultra-long chain fatty acids (C > 32) were elevated in phosphocholines from cerebelli but not liver indicating an organ-specific imbalance in fatty acid degradation and elongation pathways. By contrast, ether lipid formation was perturbed in liver towards an accumulation of alkyldiacylglycerols. The alterations in several lipid classes suggest that ACBD5, in addition to its acyl-CoA binding function, might maintain peroxisome-ER contacts in order to contribute to the regulation of anabolic and catabolic cellular lipid pathways.

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  • Impaired peroxisomal β-oxidation in ACBD5-deficient mice leads to elevations of plasma VLCFAs and significant tissue-specific alterations in lipid composition, closely resembling the lipid alterations observed in plasma and fibroblasts from RDLKD patients.

    “At the molecular level, impaired peroxisomal β-oxidation in the ACBD5-deficient mice leads to elevations of plasma VLCFAs and to significant, tissue-specific alterations in lipid composition, thus closely resembling the lipid alterations observed in plasma and fibroblasts from RDLKD patients (Darwisch et al., 2020; Granadeiro et al., 2024).”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Darwisch et al., 2020

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

    Experimental — accuracy not yet measured

  • Both ACBD5-deficient mouse strains developed retinal dystrophy characterized by photoreceptor cell loss and microglial activation.

    “Like human patients, both mouse strains developed retinal dystrophy, characterized by photoreceptor cell loss and microglial activation (Darwisch et al., 2020; Granadeiro et al., 2024).”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Darwisch et al., 2020

    The Results section reports retinal degeneration in the Acbd5−/− mouse strain, with reduced photoreceptor cells and increased microglia. The paper describes one ACBD5-deficient mouse strain, so it does not by itself support the claim that both strains developed this phenotype. No page number is available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Both Acbd5-/- mouse strains display approximately twofold increases in hexacosanoic acid (C26:0) levels in tissues and plasma, mirroring biochemical abnormalities observed in ACBD5-deficient patients.

    “Both Acbd5–/– mouse strains display approximately twofold increases in hexacosanoic acid (C26:0) levels in tissues and plasma, mirroring biochemical abnormalities observed in ACBD5-deficient patients (Darwisch et al., 2020; Granadeiro et al., 2024).”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Darwisch et al., 2020

    The Results section reports elevated C26:0 in the plasma and tissues of the Acbd5−/− mice studied, and the Discussion notes elevated very-long-chain fatty acids in ACBD5-deficient patients. But the Results specify a threefold increase, not approximately twofold, and this paper does not establish the finding for both mouse strains. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • All analyzed tissues-liver, cerebellum, and spinal cord-show increased incorporation of VLCFAs into phosphatidylcholines in Acbd5-/- mice.

    “As expected from elevated VLCFA levels, all analyzed tissues—liver, cerebellum, and spinal cord—show increased incorporation of VLCFAs into phosphatidylcholines.”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Darwisch et al., 2020

    The Results section on lipidomic profiles reports increased VLCFAs in liver and cerebellar phospholipids and describes elevated VLCFA-containing phosphatidylcholines in Acbd5−/− mice. But the Methods section on tissue lipidomics says only liver and cerebellum were analyzed; the paper does not establish increased incorporation into phosphatidylcholines in spinal cord. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Both Acbd5-/- models show cerebellar degeneration marked by Purkinje cell loss, pronounced axonal swellings, and demyelination of cerebellar white matter tracts.

    “Consistent with these motor deficits, both Acbd5–/– models show cerebellar degeneration marked by Purkinje cell loss, pronounced axonal swellings, and demyelination of cerebellar white matter tracts (Darwisch et al., 2020; Granadeiro et al., 2024), which correlates with the cerebellar symptoms typically observed in RDLKD patients.”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Darwisch et al., 2020

    The Results section ('Acbd5−/− mice develop a progressive degenerative phenotype in the cerebellum') reports Purkinje cell loss, frequent axonal swellings, and slight but significant demyelination in cerebellar homogenates from the mice studied. It does not establish demyelination specifically in cerebellar white matter tracts or findings in both models; its discussion attributes cerebellar-peduncle demyelination to patients, not these mice. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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References 72 · Cited by 32

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Authors
Darwisch, W., von Spangenberg, M., Lehmann, J., Singin, Ö., Deubert, G., Kühl, S., Roos, J., Horstmann, H., Körber, C., Hoppe, S., Zheng, H., Kuner, T., Pras-Raves, M. L., van Kampen, A. H. C., Waterham, H. R., Schwarz, K. V., Okun, J. G., Schultz, C., Vaz, F. M., & Islinger, M.
Affiliations
  • Heidelberg University (DE)
  • Amsterdam UMC Location University of Amsterdam (NL)
  • University Hospital Heidelberg (DE)
Corresponding author
Islinger, Markus
ORCID
Venue
Communications Biology
Publisher
Springer Science and Business Media LLC
Published
2020-11-26
Volume
3
Issue
1
Pages
713-713
ISSN
2399-3642 (ISSN-L)
DOI
10.1038/s42003-020-01442-x
PMC
PMC7691522
OpenAlex
W3108622438
Cited by
32
References
72
Citations by year
2026: 5 · 2025: 7 · 2024: 3 · 2023: 7 · 2022: 7 · 2021: 3
FWCI
2.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Communications Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
Funders
  • Deutsche Forschungsgemeinschaft (397476530)
  • Universität Heidelberg
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
Keywords
peroxisome biogenesis disorders, cerebellar pathology, hepatic lipid metabolism, very long chain fatty acids, ether lipids, fatty acid elongation, acyl-CoA binding, lipid homeostasis
MeSH terms
Animals, Carrier Proteins, Cerebellum, Endoplasmic Reticulum, Female, Homeostasis, Liver, Male, Mice, Knockout, Peroxisomal Disorders, Peroxisomes, Lipid Metabolism, Mice

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