Changes in Oxidised Phospholipids in Response to Oxidative Stress in <i>Microtubule-Associated Protein Tau</i> (<i>MAPT</i>) Mutant Dopamine Neurons

• Main Authors: Xanthe Bradford (Author), Hugo J. R. Fernandes (Author), Stuart G. Snowden (Author)
• Format: Book
• Published: MDPI AG, 2024-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

<i>Microtubule-associated protein Tau</i> (<i>MAPT</i>) is strongly associated with the development of neurodegenerative diseases. In addition to driving the formation of neurofibrillary tangles (NFT), mutations in the <i>MAPT</i> gene can also cause oxidative stress through hyperpolarisation of the mitochondria. This study explores the impact that <i>MAPT</i> mutation is having on phospholipid metabolism in iPSC-derived dopamine neurons, and to determine if these effects are exacerbated by mitochondrial and endoplasmic reticulum stress. Neurons that possessed a mutated copy of <i>MAPT</i> were shown to have significantly higher levels of oxo-phospholipids (Oxo-PL) than wild-type neurons. Oxidation of the hydrophobic fatty acid side chains changes the chemistry of the phospholipid leading to disruption of membrane function and potential cell lysis. In wild-type neurons, both mitochondrial and endoplasmic reticulum stress increased Oxo-PL abundance; however, in <i>MAPT</i> mutant neurons mitochondrial stress appeared to have a minimal effect. Endoplasmic reticulum stress, surprisingly, reduced the abundance of Oxo-PL in <i>MAPT</i> mutant dopamine neurons, and we postulate that this reduction could be modulated through hyperactivation of the unfolded protein response and X-box binding protein 1. Overall, the results of this study contribute to furthering our understanding of the regulation and impact of oxidative stress in Parkinson's disease pathology.

Item Description

10.3390/antiox13050508
2076-3921