Dr. Yifei Dong | University of Calgary
Dong Y, D’Mello C, Pinsky W, Lozinski BM, Kaushik DK, Ghorbani S, Moezzi D, Brown D, Melo FC, Zandee S, Vo T, Prat A, Whitehead SN, Yong VW. Oxidized phosphatidylcholines found in multiple sclerosis lesions mediate neurodegeneration and are neutralized by microglia. Nature Neuroscience. 24, 489-503 (2021).
Oxidized phosphatidylcholines identified as potent drivers of neurodegeneration in Multiple sclerosis
Neurodegeneration occurring in multiple sclerosis (MS) contributes to the progression of disability. It is therefore important to identify and neutralize the mechanisms that promote neurodegeneration in this disease. In this new study, Yifei Dong and colleagues report that Oxidized phosphatidylcholines (OxPC), molecules found in MS lesions and previously identified as end-products of oxidative stress, are potent drivers of neurodegeneration.
In the healthy brain, lipid-rich myelin sheaths the axons of neurons to aid electrical impulse conduction and provide metabolic support. In MS, this myelin coat is disrupted, and the myelin debris in lesions require clearance by microglia, which are immune cells of the brain. In this study, the researchers show OxPCs are novel and potent mediators of loss of myelin and neurodegeneration that directly cause death of neurons and oligodendrocytes, which are the myelin sheath producing cells. OxPCs killed human derived oligodendrocytes and neurons in culture and caused demyelination and neurodegeneration upon injection into the mouse spinal cord white matter.
OxPC deposition occurs in multiple neurological diseases including MS, frontotemporal dementia, ALS, and in spinal cord injury. Thus, they may be an important underlying driver of neurodegeneration across multiple diseases. Indeed, OxPCs are found to promote tissue injury in a number of non-neurological diseases such as atherosclerosis, non-alcoholic fatty liver disease, and lung fibrosis.
This publication also provides evidence that therapeutic neutralization of OxPCs may help to stop the neurodegenerative process and thus reduce the health burden of individuals afflicted with MS and other neurological conditions. Given microglia protect the brain from OxPC insult, therapeutic modulation of microglia function to remove OxPCs may be another promising avenue to treat neurodegeneration. Moreover, imaging mass spectrometry identified multiple OxPC species in MS lesions. Recent studies show different OxPCs have unique pro-inflammatory properties and thus additional investigation is needed to understand how unique OxPCs individually or in combination contribute to sustained neuroinflammation or neurodegeneration in MS and other central nervous system diseases. Together, these results highlight a new underlying mechanism of neurodegeneration that upon clinical translation may benefit multiple brain diseases.
Dr. Yifei Dong
Dr. Yifei Dong performed this research as a post-doctoral fellow in the laboratory of Dr. Von Wee Yong at the University of Calgary. conceived this project and performed most of the experimentation and data analysis that resulted in this publication. He developed the models used to study OxPCs in vitro and in vivo, and these protocols are recently published in a Star Protocols (Dong et al. STAR Protocols. 2021). The initial draft of the manuscript was written by Dr. Dong, and he was critically involved with all the subsequent edits and revisions. All the data and figures were also collated and made by Dr. Dong.
Source of funding
This research is funded by CIHR and MS Society of Canada.