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Mitochondrial and Endoplasmic Reticulum Stress Trigger Triglyceride Accumulation in Models of Parkinson's Disease Independent of Mutations in MAPT.

Published version
Peer-reviewed

Type

Article

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Authors

Fernandes, Hugo JR 
Kent, Josh P 
Bruntraeger, Michaela 
Bassett, Andrew R 

Abstract

The metabolic basis of Parkinson's disease pathology is poorly understood. However, the involvement of mitochondrial and endoplasmic reticulum stress in dopamine neurons in disease aetiology is well established. We looked at the effect of rotenone- and tunicamycin-induced mitochondrial and ER stress on the metabolism of wild type and microtubule-associated protein tau mutant dopamine neurons. Dopamine neurons derived from human isolated iPSCs were subjected to mitochondrial and ER stress using RT and TM, respectively. Comprehensive metabolite profiles were generated using a split phase extraction analysed by reversed phase lipidomics whilst the aqueous phase was measured using HILIC metabolomics. Mitochondrial and ER stress were both shown to cause significant dysregulation of metabolism with RT-induced stress producing a larger shift in the metabolic profile of both wild type and MAPT neurons. Detailed analysis showed that accumulation of triglycerides was a significant driver of metabolic dysregulation in response to both stresses in both genotypes. Whilst the consequence is similar, the mechanisms by which triglyceride accumulation occurs in dopamine neurons in response to mitochondrial and ER stress are very different. Thus, improving our understanding of how these mechanisms drive the observed triglyceride accumulation can potentially open up new therapeutic avenues.

Description

Keywords

LC-MS, Parkinson’s disease, endoplasmic reticulum stress, metabolomics, mitochondrial stress, triglyceride

Journal Title

Metabolites

Conference Name

Journal ISSN

2218-1989
2218-1989

Volume Title

13

Publisher

MDPI AG
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/P028195/1)