Cholesterol homeostasis and oxidative stress-related novel plasma biomarkers for MSA patients

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Abstract Multiple system atrophy (MSA) is an atypical parkinsonism that mimics the clinical manifestation of Parkinson’s disease (PD) but is characterized by distinct pathological hallmarks and poor medication response. Identifying reliable biomarkers for MSA facilitates differential diagnosis and promotes targeted treatments. Here, we profiled plasma-derived extracellular vesicle (EV) proteomics in patients with MSA or PD and healthy controls (HC), based on liquid chromatography‒mass spectrometry (LC‒MS/MS). A modified linear programming system termed Biomedical Oriented Logistic Dantzig (BOLD) Selector was implemented for the identification of the EV proteins that were significantly associated with MSA through an oversaturated proteomic dataset comprising 1272 entries. As a result, the top-ranked EV protein candidates incorporated into our constructed logistic regression formula for differentiating MSA patients with HC were LCAT, CRKL, Kallistatin and CSE1L, and APOE, ALDH4A1, ABCC4, and kallistatin for separating MSA from typical PD patients. These EV proteins are most strongly attributed to “cholesterol transport” by gene ontology analysis. The other major biological processes highlighted for these candidates include modulators for oxidative stress, inflammation, and demyelination processes. Innovative therapeutic approaches targeting these candidates aiming at regulating cholesterol balance, reducing oxidative stress, and alleviating glial inflammation hold promise for neuroprotection against the lethal neurodegenerative disorders.

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