Scholarlink

<p>Despite the lipid-rich nature of the brain, defining the role of lipid metabolism in neurodegenerative disease and targeting lipid metabolic pathways for disease modification are in their infancy. In Parkinson’s disease, Lewy body dementia, and other synucleinopathies, disease-associated forms of α-synuclein (αS) alter fatty acid (FA) metabolism, increasing monounsaturated FA-containing lipids. This disequilibrium in membrane fatty acyl composition results in aberrant αS:membrane interactions. We report treating PD patient neurons with myristic acid (C14:0) induces lipid metabolism modifications correcting abnormal PD-associated membrane composition and reversing PD-relevant phenotypes. C14:0 conditioning reduced Lewy-like αS inclusions; reduced abnormal pSer129 αS; corrected excess αS at membranes; and restored native αS tetramer:monomer homeostasis. Using nuclear magnetic resonance, we established C14:0 as correcting abnormal αS vesicle membranes dwell time in vitro, correlating with less pathogenic αS aggregation. Mechanistically, C14:0 rescued PD neuron phenotypes through remodeling the PD-associated lipidome, eliciting beneficial effects by increasing shorter, saturated fatty acyl-lipids.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Lipid membrane remodeling by myristic acid treatment reverses Parkinson’s disease α-synuclein phenotypes in patient neurons

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月14日

查看全文
  • Julian Avila Pacheco,
  • Gleidia Sauli,
  • Luis Fonseca-Ornelas,
  • Haley Cirka,
  • Deepa Kumari,
  • Morgan Hazo,
  • Sarah Jeanfavre,
  • Pedro H. Vendramini,
  • Christina R. Muratore,
  • Clary B. Clish,
  • Dennis Selkoe,
  • Saranna Fanning

摘要

Despite the lipid-rich nature of the brain, defining the role of lipid metabolism in neurodegenerative disease and targeting lipid metabolic pathways for disease modification are in their infancy. In Parkinson’s disease, Lewy body dementia, and other synucleinopathies, disease-associated forms of α-synuclein (αS) alter fatty acid (FA) metabolism, increasing monounsaturated FA-containing lipids. This disequilibrium in membrane fatty acyl composition results in aberrant αS:membrane interactions. We report treating PD patient neurons with myristic acid (C14:0) induces lipid metabolism modifications correcting abnormal PD-associated membrane composition and reversing PD-relevant phenotypes. C14:0 conditioning reduced Lewy-like αS inclusions; reduced abnormal pSer129 αS; corrected excess αS at membranes; and restored native αS tetramer:monomer homeostasis. Using nuclear magnetic resonance, we established C14:0 as correcting abnormal αS vesicle membranes dwell time in vitro, correlating with less pathogenic αS aggregation. Mechanistically, C14:0 rescued PD neuron phenotypes through remodeling the PD-associated lipidome, eliciting beneficial effects by increasing shorter, saturated fatty acyl-lipids.