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

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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.