Cuprizone and EAE mouse frontal cortex proteomics revealed proteins altered in multiple sclerosis.

Area of Science:

• Neuroscience
• Proteomics
• Biochemistry

Background:

• Multiple sclerosis (MS) is a demyelinating disease affecting the central nervous system.
• Understanding protein alterations in MS is crucial for developing diagnostic and therapeutic strategies.
• The frontal cortex, often spared in MS, offers a unique perspective on disease mechanisms.

Purpose of the Study:

• To compare protein alterations in two distinct MS experimental models: cuprizone (demyelination) and experimental autoimmune encephalomyelitis (EAE, immune-mediated).
• To identify novel protein targets for diagnosis, prognosis, or treatment in human MS.
• To investigate the role of specific proteins, like legumain, in MS pathology.

Main Methods:

• Quantitative proteomics using TMT-labelling and mass spectrometry.
• Label-free proteomics for fold change verification.
• Immunohistochemistry on post-mortem MS brain tissue.
• Analysis of cerebrospinal fluid (CSF) from MS patients and controls.

Main Results:

• 1871 proteins overlapped between the cuprizone and EAE models, but few similarities in regulated proteins and pathways were observed.
• Legumain and C1Q complement proteins were upregulated in the cuprizone model; hemopexin was upregulated in the EAE model.
• Legumain expression was significantly higher in active MS lesions in post-mortem brain tissue, correlating with lesion activity.

Conclusions:

• Legumain is a promising therapeutic target for MS, with inhibitors potentially beneficial.
• Despite increased expression in brain lesions, CSF levels of legumain, C1q, and hemopexin did not differ significantly between MS patients and controls.