Controlling peroxisome-ER contacts - Molecular mechanisms to regulate peroxisome tethering and distribution
Lead Research Organisation:
UNIVERSITY OF EXETER
Department Name: Biosciences
Abstract
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.
Publications
Islinger M
(2020)
The diversity of ACBD proteins - From lipid binding to protein modulators and organelle tethers.
in Biochimica et biophysica acta. Molecular cell research
Azadi AS
(2020)
A Functional SMAD2/3 Binding Site in the PEX11ß Promoter Identifies a Role for TGFß in Peroxisome Proliferation in Humans.
in Frontiers in cell and developmental biology
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
MR/N013794/1 | 01/10/2016 | 30/09/2025 | |||
2073760 | Studentship | MR/N013794/1 | 01/10/2018 | 30/09/2022 | Suzan Kors |
Title | Site-specific phospho-antibody |
Description | We developed a site-specific phospho-antibody (Eurogentec) for the peroxisomal protein ACBD5. We confirmed the specificity of the antibody. |
Type Of Material | Antibody |
Year Produced | 2020 |
Provided To Others? | No |
Impact | Having this antibody allows us now to determine under which conditions the specific site is (non-)phosphorylated. |
Description | I'm a Scientist - chatting with school students |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | I took part in the MRC Medical Research Zone, from I'm a Scientist, an online, student-led STEM enrichment activity. It connects school students with scientists through real-time text based chats - to engage students with science during the pandemic. The students can ask the scientists anything, about their research, science in general, career, as well as hobbies and favourite food, so that they discover that scientists are 'real' human beings and that live sciences are fascinating and worthwhile to engage with. During the month November several researchers took part in live chats with students, a total of 467 students across the UK logged into the activity. |
Year(s) Of Engagement Activity | 2020 |
URL | https://imascientist.org.uk/ |
Description | Zellweger UK (ZUK) charity family meetings |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | The charity Zellweger UK (ZUK) supports families and patients suffering from severe organelle (peroxisome)-based disorders such as Zellweger Spectrum Disorders. The family meeting/conference brings together families/carers and patients as well as international scientists and physicians. In 2018 24 families came together to listen to talks from and discuss with scientists and physicians. The charity is also contributing to our education/teaching activities in Biosciences (Module BIO3086 "Cell Biology of Disease") with a patient-centred session. Our group (Prof. Michael Schrader) is engaged in outreach activities/widening participation and prepared joint publications to increase awareness of Zellweger Spectrum Disorders and the need for research and treatment options. |
Year(s) Of Engagement Activity | 2018,2019 |
URL | https://www.zellweger.org.uk/ |