Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917816 (mental retardation)
 15,867 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long-chain acyl-CoA synthetases (ACSLs) convert long-chain fatty acids to acyl-CoAs, the activated substrates essential in various metabolic and signaling pathways. Mutations in ACSL4 are associated with non-syndromic X-linked mental retardation (MRX). However, the developmental functions of ACSL4 and how it is involved in the pathogenesis of MRX remain largely unknown. The Drosophila ACSL-like protein is highly homologous to human ACSL3 and ACSL4, and we designate it as dAcsl. In this study, we demonstrate that dAcsl and ACSL4 are highly conserved in terms of ACSL4's ability to substitute the functions of dAcsl in organismal viability, lipid storage and the neural wiring in visual center. In neurodevelopment, decapentaplegic (Dpp, a BMP-like molecule) production diminished specifically in the larval brain of dAcsl mutants. Consistent with the Dpp reduction, the number of glial cells and neurons dramatically decreased and the retinal axons mis-targeted in the visual cortex. All these defects in Drosophila brain were rescued by the wild-type ACSL4 but not by the mutant products found in MRX patients. Interestingly, expression of an MRX-associated ACSL4 mutant form in a wild-type background led to the lesions in visual center, suggesting a dominant negative effect. These findings validate Drosophila as a model system to reveal the connection between ACSL4 and BMP pathway in neurodevelopment, and to infer the pathogenesis of ACSL4-related MRX.
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PMID:Analyses of mental dysfunction-related ACSl4 in Drosophila reveal its requirement for Dpp/BMP production and visual wiring in the brain. 1961 35

Fatty acid metabolism plays an important role in brain development and function. Mutations in acyl-CoA synthetase long-chain family member 4 (ACSL4), which converts long-chain fatty acids to acyl-CoAs, result in nonsyndromic X-linked mental retardation. ACSL4 is highly expressed in the hippocampus, a structure critical for learning and memory. However, the underlying mechanism by which mutations of ACSL4 lead to mental retardation remains poorly understood. We report here that dAcsl, the Drosophila ortholog of ACSL4 and ACSL3, inhibits synaptic growth by attenuating BMP signaling, a major growth-promoting pathway at neuromuscular junction (NMJ) synapses. Specifically, dAcsl mutants exhibited NMJ overgrowth that was suppressed by reducing the doses of the BMP pathway components, accompanied by increased levels of activated BMP receptor Thickveins (Tkv) and phosphorylated mothers against decapentaplegic (Mad), the effector of the BMP signaling at NMJ terminals. In addition, Rab11, a small GTPase involved in endosomal recycling, was mislocalized in dAcsl mutant NMJs, and the membrane association of Rab11 was reduced in dAcsl mutant brains. Consistently, the BMP receptor Tkv accumulated in early endosomes but reduced in recycling endosomes in dAcsl mutant NMJs. dAcsl was also required for the recycling of photoreceptor rhodopsin in the eyes, implying a general role for dAcsl in regulating endocytic recycling of membrane receptors. Importantly, expression of human ACSL4 rescued the endocytic trafficking and NMJ phenotypes of dAcsl mutants. Together, our results reveal a novel mechanism whereby dAcsl facilitates Rab11-dependent receptor recycling and provide insights into the pathogenesis of ACSL4-related mental retardation.
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PMID:dAcsl, the Drosophila ortholog of acyl-CoA synthetase long-chain family member 3 and 4, inhibits synapse growth by attenuating bone morphogenetic protein signaling via endocytic recycling. 2455 21