The XLMR gene ACSL4 plays a role in dendritic spine architecture

Meloni, Ilaria; Parri, Veronica; Filippis, Roberta De; Ariani, Francesca; Artuso, Rosangela; Bruttini, Mirella; Katzaki, Eleni; Longo, Ilaria; Mari, Francesca; Bellan, Cristiana; Dotti, Carlos G.; Renieri, Alessandra

doi:10.1016/j.neuroscience.2008.11.056

Cited by 35 publications

(38 citation statements)

References 54 publications

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“…A recent study demonstrates the presence of a new long-chain acyl-CoA synthetase (ACSL4) isoenzyme that localizes specifically in the ER of neurons. Its deficiency increases the percentage of filopodia and reduces the percentage of mature spines (21), in accordance with our results. This highlights the importance of fatty acid metabolism in spinogenesis and suggests that ACSL could provide the substrate necessary for ceramide synthesis in the ER of neurons.…”

Section: Discussionsupporting

confidence: 93%

Ceramide Levels Regulated by Carnitine Palmitoyltransferase 1C Control Dendritic Spine Maturation and Cognition

Carrasco

Sahún

McDonald

et al. 2012

Journal of Biological Chemistry

101

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Background: CPT1C is highly expressed in hippocampus, but its cellular and physiological function is unknown. Results: CPT1C overexpression increases ceramide levels, and CPT1C deficiency impairs dendritic spine morphology and spatial learning. Conclusion: Regulation of ceramide levels by CPT1C is necessary for proper spine maturation. Significance: We describe a new function of CPT1C in cognition.

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Section: Discussionsupporting

confidence: 93%

Ceramide Levels Regulated by Carnitine Palmitoyltransferase 1C Control Dendritic Spine Maturation and Cognition

Carrasco

Sahún

McDonald

et al. 2012

Journal of Biological Chemistry

101

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“…6, 8). The atrophic NMJ synapses in dAcsl mutants are consistent with the reduced number of dendritic spines in cultured hippocampal neurons with Acsl4 knocked down by RNA interference (Meloni et al, 2009). Importantly, the synaptic defects in dAcsl mutants can be fully rescued by human ACSL4, demonstrating a conserved synaptic function between Drosophila dAcsl and human ACSL4.…”

Section: Discussion Dacsl Mutations Primarily Impair Retrograde Axonasupporting

confidence: 62%

“…ACSL4 belongs to a family of enzymes that convert long-chain fatty acids to acyl-CoAs that participate in multiple biosynthetic, metabolic, and cellular signaling pathways (Coleman et al, 2002). The enzyme is highly expressed in the hippocampus, a structure critical for learning and memory, where it is required for dendritic spine formation (Cao et al, 2000b;Meloni et al, 2002Meloni et al, , 2009. The mechanisms by which mutations of ACSL4 lead to MR, however, are still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

DrosophilaAcyl-CoA Synthetase Long-Chain Family Member 4 Regulates Axonal Transport of Synaptic Vesicles and Is Required for Synaptic Development and Transmission

Liu

Huang²,

Zhang³

et al. 2011

J. Neurosci.

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Acyl-CoA synthetase long-chain family member 4 (ACSL4) converts long-chain fatty acids to acyl-CoAs that are indispensable for lipid metabolism and cell signaling. Mutations in ACSL4 cause nonsyndromic X-linked mental retardation. We previously demonstrated that Drosophila dAcsl is functionally homologous to human ACSL4, and is required for axonal targeting in the brain. Here, we report that Drosophila dAcsl mutants exhibited distally biased axonal aggregates that were immunopositive for the synaptic-vesicle proteins synaptotagmin (Syt) and cysteine-string protein, the late endosome/lysosome marker lysosome-associated membrane protein 1, the autophagosomal marker Atg8, and the multivesicular body marker Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate). In contrast, the axonal distribution of mitochondria and the cell adhesion molecule Fas II (fasciclin II) was normal. Electron microscopy revealed accumulation of prelysomes and multivesicle bodies. These aggregates appear as retrograde instead of anterograde cargos. Live imaging analysis revealed that dAcsl mutations increased the velocity of anterograde transport but reduced the flux, velocity, and processivity of retrograde transport of Syt-enhanced green fluorescent protein-labeled vesicles. Immunohistochemical and electrophysiological analyses showed significantly reduced growth and stability of neuromuscular synapses, and impaired glutamatergic neurotransmission in dAcsl mutants. The axonal aggregates and synaptic defects in dAcsl mutants were fully rescued by neuronal expression of human ACSL4, supporting a functional conservation of ACSL4 across species in the nervous system. Together, our findings demonstrate that dAcsl regulates axonal transport of synaptic vesicles and is required for synaptic development and function. Defects in axonal transport and synaptic function may account, at least in part, for the pathogenesis of ACSL4-related mental retardation.

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“…ACSL4 protein has two variants: a ubiquitously expressed short form (Kang et al, 1997), and a brain-specific long form that is highly expressed in the hippocampus, a crucial region for memory (Meloni et al, 2002). Indeed, ACSL4 has been shown to play an important role in synaptic spine formation (Meloni et al, 2009). However, it is unclear how mutations in ACSL4 lead to intellectual disability.…”

Section: Introductionmentioning

confidence: 99%

Acsl, the Drosophila ortholog of intellectual-disability-related ACSL4, inhibits synaptic growth by altered lipids

Huang

Lam

et al. 2016

Journal of Cell Science

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Nervous system development and function are tightly regulated by metabolic processes, including the metabolism of lipids such as fatty acids. Mutations in long-chain acyl-CoA synthetase 4 (ACSL4) are associated with non-syndromic intellectual disabilities. We previously reported that Acsl, the Drosophila ortholog of mammalian ACSL3 and ACSL4, inhibits neuromuscular synapse growth by suppressing bone morphogenetic protein (BMP) signaling. Here, we report that Acsl regulates the composition of fatty acids and membrane lipids, which in turn affects neuromuscular junction (NMJ) synapse development. Acsl mutant brains had a decreased abundance of C16:1 fatty acyls; restoration of Acsl expression abrogated NMJ overgrowth and the increase in BMP signaling. A lipidomic analysis revealed that Acsl suppressed the levels of three lipid raft components in the brain, including mannosyl glucosylceramide (MacCer), phosphoethanolamine ceramide and ergosterol. The MacCer level was elevated in Acsl mutant NMJs and, along with sterol, promoted NMJ overgrowth, but was not associated with the increase in BMP signaling in the mutants. These findings suggest that Acsl inhibits NMJ growth by stimulating C16:1 fatty acyl production and concomitantly suppressing raft-associated lipid levels.

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The XLMR gene ACSL4 plays a role in dendritic spine architecture

Cited by 35 publications

References 54 publications

Ceramide Levels Regulated by Carnitine Palmitoyltransferase 1C Control Dendritic Spine Maturation and Cognition

Ceramide Levels Regulated by Carnitine Palmitoyltransferase 1C Control Dendritic Spine Maturation and Cognition

DrosophilaAcyl-CoA Synthetase Long-Chain Family Member 4 Regulates Axonal Transport of Synaptic Vesicles and Is Required for Synaptic Development and Transmission

Acsl, the Drosophila ortholog of intellectual-disability-related ACSL4, inhibits synaptic growth by altered lipids

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