Controlling peroxisome-ER contacts - Molecular mechanisms to regulate peroxisome tethering and distribution

细胞器合作研究是现代细胞生物学和生物医学科学中一个令人兴奋的新领域，因为它与细胞器功能密切相关，并对发育和生理过程产生影响。过氧化物酶体在脂质代谢、信号传导、对抗氧化应激和衰老中的重要保护作用最近已经出现（Islinger & Schrader 2011，Curr Biol.21：R800; Schrader等人2015，J Inherit Metab Dis 38：681）。过氧化物酶体功能障碍与神经变性、失明和耳聋有关，但其分子机制和病理生理学改变尚不清楚，缺乏有效的治疗方法。我们的工作揭示了过氧化物酶体通过膜接触位点与内质网（ER）相互作用的第一个分子机制（Costello 2017，J Cell Biol 216：331）。这些接触，这取决于新的脂质结合膜蛋白，ACBD 5和ACBD 4，是重要的过氧化物酶体-ER代谢合作，在脂质合成，例如髓鞘脂质，并在膜动力学和定位的过氧化物酶体。ACBD 5缺陷型患者最近已被鉴定，其特征为视网膜营养不良、白色疾病和极长链脂肪酸的积累，这些脂肪酸只能在过氧化物酶体中降解。我们的研究结果现在使我们能够首次探索ACBD 4/5依赖性过氧化物酶体-ER协会和合作脂质代谢在神经元功能，突触可塑性和神经变性中的作用。这个多学科项目结合了尖端的神经生物学，成像和建模方法，以确定ACBD 4/5对神经元发育和突触可塑性的影响。这项工作将有助于揭示新的基本生物学和生物医学原理，了解ACBD 5/4的功能和过氧化物酶体-ER合作的机制及其对神经元功能和神经退行性疾病的影响。

Research on organelle cooperation represents an exciting new field in modern cell biology and biomedical sciences because of its close relation to organelle functionality and its impact on developmental and physiological processes. Vital, protective roles of peroxisomes in lipid metabolism, signalling, the combat of oxidative stress and ageing have emerged recently (Islinger & Schrader 2011, Curr Biol. 21:R800; Schrader et al. 2015, J Inherit Metab Dis 38:681). Peroxisomal dysfunction has been linked to neurodegeneration, loss of sight and deafness, but the molecular mechanisms and pathophysiological alterations are not well understood, and effective treatment for patients is lacking. Our work has revealed the first molecular mechanism for the interaction of peroxisomes with the endoplasmic reticulum (ER) via membrane contact sites (Costello 2017, J Cell Biol 216:331). These contacts, which depend on novel lipid-binding membrane proteins, ACBD5 and ACBD4, are important for peroxisome-ER metabolic cooperation in lipid synthesis, e.g. of myelin sheath lipids, and in membrane dynamics and positioning of peroxisomes. ACBD5-deficient patients have been recently identified, and are characterised by retinal dystrophy, white matter disease and accumulation of very-long-chain fatty acids, which can only be degraded in peroxisomes. Our findings now enable us for the first time to explore the role of ACBD4/5-dependent peroxisome-ER associations and cooperative lipid metabolism in neuronal function, synaptic plasticity and neurodegeneration. This multi-disciplinary project combines cutting-edge neurobiological, imaging and modelling approaches to determine the impact of ACBD4/5 on neuronal development and synaptic plasticity. This work will help to unravel new basic biological and biomedical principles, to understand the functions of ACBD5/4 and the mechanisms of peroxisome-ER cooperation and their impact on neuronal function and neurodegenerative disorders.