Ataxia with giant axonopathy in Acbd5 -deficient mice halted by adeno-associated virus gene therapy
Open accessAbstract
Acyl-CoA binding domain containing 5 (ACBD5) is a critical player in handling very long chain fatty acids (VLCFA) en route for peroxisomal β-oxidation. Mutations in ACBD5 lead to the accumulation of VLCFA and patients present retinal dystrophy, ataxia, psychomotor delay and a severe leukodystrophy. Using CRISPR/Cas9, we generated and characterized an Acbd5 Gly357* mutant allele. Gly357* mutant mice recapitulated key features of the human disorder, including reduced survival, impaired locomotion and reflexes, loss of photoreceptors, and demyelination. The ataxic presentation of Gly357* mice involved the loss of cerebellar Purkinje cells and a giant axonopathy throughout the CNS. Lipidomic studies provided evidence for the extensive lipid dysregulation caused by VLCFA accumulation. Following a proteomic survey, functional studies in neurons treated with VLCFA unravelled a deregulated cytoskeleton with reduced actin dynamics and increased neuronal filopodia. We also show that an adeno-associated virus-mediated gene delivery ameliorated the gait phenotypes and the giant axonopathy, also improving myelination and astrocyte reactivity. Collectively, we established a mouse model with significance for VLCFA-related disorders. The development of relevant neuropathological outcomes enabled the understanding of mechanisms modulated by VLCFA and the evaluation of the efficacy of preclinical therapeutic interventions.
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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 Granadeiro et al., 2024
The section “Disruption of CNS lipid homeostasis in Gly357* mice” (page unavailable) reports a twofold C26:0 increase in the spinal cords of Gly357* mice. The Discussion (page unavailable) also reports VLCFA accumulation in ACBD5-deficient patients and the other mouse strain, but does not establish a twofold C26:0 increase in both strains across tissues and plasma. (LLM, conf=0.88)
Experimental — accuracy not yet measuredImpaired 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 Granadeiro et al., 2024
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 measuredBoth 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 Granadeiro et al., 2024
The section “Loss of Acbd5 causes retina defects and ataxia” reports photoreceptor degeneration in Gly357* mice, supporting retinal dystrophy in the strain studied here. The paper reports microglial activation in the spinal cord, not the retina, and does not establish retinal findings for both mouse strains. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSignificant astrocyte and microglial activation was observed in the cerebellum, with additional neuroinflammatory changes identified in the telencephalon of Acbd5Gly357* mice.
“Significant astrocyte and microglial activation was observed in the cerebellum, with additional neuroinflammatory changes identified in the telencephalon of Acbd5Gly357* mice (Granadeiro et al., 2024).”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Granadeiro et al., 2024
The ‘Extensive gliosis underscores CNS pathology’ section reports increased astrocyte and microglial reactivity in the spinal cords of Gly357* mice; Figure 4 also measures these markers in spinal cords (page numbers unavailable). The paper reports cerebellar demyelination, but the passages do not establish cerebellar astrocyte or microglial activation or telencephalic neuroinflammation. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNeuroinflammation is evident in both ACBD5-deficient mouse models.
“Neuroinflammation, a hallmark of leukodystrophies, is also evident in both mouse models.”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Granadeiro et al., 2024
The section ‘Extensive gliosis underscores CNS pathology in Gly357* mice’ (page unavailable) reports increased astrocyte reactivity and microgliosis, supporting neuroinflammation in the Gly357* model. The paper’s discussion mentions an Acbd5 tm1a mutant, but the passages found do not establish neuroinflammation in that second model; ‘both mouse models’ is therefore unsupported by this source. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Both ACBD5-deficient mouse models exhibit prominent neurological phenotypes, including hindlimb-clasping reflex loss and ataxia, closely reflecting the locomotor dysfunction seen in patients.
“Both ACBD5-deficient mouse models exhibit prominent neurological phenotypes, including hindlimb-clasping reflex loss and ataxia, closely reflecting the locomotor dysfunction seen in patients.”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Granadeiro et al., 2024
The Results section, “Loss of Acbd5 causes retina defects and ataxia” (page unavailable), reports limb clasping and progressive locomotor and coordination defects in Gly357* mice. The Introduction says these mice mimic key aspects of the human disorder. But the paper does not report clasping or ataxia in the other Acbd5-deficient model, tm1a, so it does not support the claim that both models exhibit those phenotypes. (LLM, conf=0.88)
Experimental — accuracy not yet measuredACBD5-deficient mice develop significant gliosis throughout the white and gray matter of the telencephalon.
“Moreover, their ACBD5-deficient mice developed a significant gliosis throughout the white and gray matter of the telencephaolon, which correlates with the brain degeneration observed in RDLKD patients.”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Granadeiro et al., 2024
The section “Extensive gliosis underscores CNS pathology in Gly357* mice” reports gliosis in both grey and white matter of the spinal cord by one year of age. It does not establish gliosis throughout the white and grey matter of the telencephalon; the cited sentence places the finding in a different anatomical region. Page numbers were not available in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredBoth 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 Granadeiro et al., 2024
The sections on retina defects and ataxia, giant axon swellings, and CNS demyelination (page numbers unavailable) report Purkinje cell loss, axonal swellings, and cerebellar white-matter demyelination in the Gly357* mouse model. This paper does not establish all three findings in both models named by the citing sentence. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThese complex lipid changes are particularly pronounced in the spinal cord of Acbd5Gly357* mice.
“These complex lipid changes are particularly pronounced in the spinal cord of Acbd5Gly357* mice (Granadeiro et al., 2024).”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Granadeiro et al., 2024
The section ‘Disruption of CNS lipid homeostasis in Gly357* mice’ reports 139 dysregulated lipids in mutant spinal cords and describes the changes as complex. It does not establish that the changes are particularly pronounced in the spinal cord relative to other tissues. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn addition to marked accumulation of VLCFAs in phosphatidylcholines and triglycerides in Acbd5-/- mice, more subtle alterations are observed in lipid species with shorter chain lengths and across various lipid classes.
“In addition to the marked accumulation of VLCFAs in phosphatidylcholines and triglycerides in Acbd5–/– mice, more subtle alterations are also observed in lipid species with shorter chain lengths and across various lipid classes.”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Granadeiro et al., 2024
The ‘Disruption of CNS lipid homeostasis in Gly357* mice’ section reports VLCFA-containing lipid accumulation, changes in several lipid classes, and alterations in lipids without VLCFAs. It identifies phosphatidylcholines as an altered class, but our copy does not establish the claimed marked accumulation specifically in phosphatidylcholines and triglycerides. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAcbd1-/- mice exhibit a roughly sixfold increase in C26:0 levels in the spinal cord, approximately three times higher than in Acbd5-/- mice.
“These molecular differences are also reflected in vivo: Acbd1–/– mice exhibit a roughly sixfold increase in C26:0 levels in the spinal cord—approximately three times higher than in Acbd5–/– mice—whereas Acbd2–/– mice show no such accumulation (Pujol et al., 2004; Granadeiro et al., 2024).”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Granadeiro et al., 2024
In “Disruption of CNS lipid homeostasis in Gly357* mice” (page not provided), the paper reports a twofold increase in spinal-cord C26:0 in Acbd5-deficient mice. It does not report a sixfold increase in Acbd1–/– mice or directly establish the claimed threefold comparison. (LLM, conf=0.88)
Experimental — accuracy not yet measuredACBD5-deficient mice show myelin thinning in the spinal cord and giant axonal swellings accompanied by disorganized axonal filament proteins.
“Brites and colleagues further reported myelin thinning in the spinal cord and the presence of giant axonal swellings accompanied by disorganized axonal filament proteins, highlighting structural disruptions likely contributing to motor impairment (Granadeiro et al., 2024).”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Granadeiro et al., 2024
Preclinical studies using AAV-mediated delivery of a functional ACBD5 gene have shown significant improvement in disease progression in the Acbd5Gly357* mouse model.
“Gene therapy offers a promising avenue; preclinical studies using adeno-associated virus (AAV)-mediated delivery of a functional ACBD5 gene have shown significant improvement in disease progression in the Acbd5Gly357* mouse model (Granadeiro et al., 2024).”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Granadeiro et al., 2024
DHA levels were only slightly reduced in liver lysophosphatidylcholines, and no differences were detected in nervous tissue between Acbd5-/- and wild-type mice.
“However, DHA levels were only slightly reduced in liver lysophosphatidylcholines, and no differences were detected in nervous tissue between Acbd5–/– and wild-type mice (Darwisch et al., 2020; Granadeiro et al., 2024), suggesting compensatory mechanisms, possibly via upregulated DHA synthesis.”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Granadeiro et al., 2024
The ‘Disruption of CNS lipid homeostasis in Gly357* mice’ section reports lipid changes in spinal cords, but does not identify DHA levels or report a DHA comparison with wild-type mice. Searches for DHA and liver lysophosphatidylcholines found no passage establishing the claimed slight reduction in liver or absence of a difference in nervous tissue. (LLM, conf=0.75)
Experimental — accuracy not yet measuredAcbd2-/- mice show no accumulation of C26:0 in the spinal cord.
“These molecular differences are also reflected in vivo: Acbd1–/– mice exhibit a roughly sixfold increase in C26:0 levels in the spinal cord—approximately three times higher than in Acbd5–/– mice—whereas Acbd2–/– mice show no such accumulation (Pujol et al., 2004; Granadeiro et al., 2024).”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Granadeiro et al., 2024
The section ‘Disruption of CNS lipid homeostasis in Gly357* mice’ reports a twofold spinal-cord C26:0 increase in Acbd5-mutant mice, not a result for Acbd2−/− mice. The Introduction mentions Abcd1:Abcd2 double-knockout mice but gives no spinal-cord C26:0 measurement for them; a search for Acbd2−/− and Abcd2 knockout C26:0 found no passage establishing the claimed absence of accumulation. Page numbers were not available in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Cited by
Sorted by citations
Kors, S., Schuster, M., Maddison, D. C., Kilaru, S., Schrader, T. A., Costello, J. L., Islinger, M., Smith, G. A., & Schrader, M. (2024) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2024.119843 · Cited by 12 · see citing works
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
- Authors
- Granadeiro, L., Zarralanga, V. E., Rosa, R., Franquinho, F., Lamas, S., & Brites, P.
- Affiliations
- Neurolipid Biology, Instituto de Investigação e Inovação em Saúde da Universidade do Porto - i3S and Instituto de Biologia Molecular e Celular - IBMC , 4200-135 Porto , Portugal
- Universidade do Porto (PT)
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto (PT)
- Corresponding author
- Brites, Pedro
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2023-12-08
- Volume
- 147
- Issue
- 4
- Pages
- 1457-1473
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W4389499458
- Cited by
- 9
- References
- 14
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 1
- FWCI
- 1.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fundação para a Ciência e a Tecnologia-FCT (SFRH/BD/138968/2018)
- National Funds (UIDB/04293/2020)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- very long chain fatty acids, peroxisomal beta-oxidation, adeno-associated virus gene therapy, CRISPR/Cas9 mouse model, Purkinje cells, demyelination, retinal dystrophy, leukodystrophy, lipidomics, actin cytoskeleton, astrocyte activation, myelination, neurodegeneration
- MeSH terms
- Dependovirus, Adrenoleukodystrophy, Animals, Ataxia, Fatty Acids, Humans, Genetic Therapy, Proteomics, Mice
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