Searching for Reliable Premortem Protein Biomarkers for Prion Diseases

Progress and Challenges to Date

Di Ma; Lingjun Li

Expert Rev Proteomics. 2012;9(3):267-280.

Five-year View

At the current stage, discovery of biomarkers for early detection of prion diseases has been mostly confined to the general profiling of the proteome in easily accessible biological fluids. Now that the important role of glycosylation in neurodegenerative diseases has been revealed, the application of MS-based glycoproteomics holds promise in the identification of new glycoprotein biomarkers. Moreover, new approaches allowing the distinction of a prion disease-related glycosylated form of a potential biomarker from the non-glycosylated form or other isoforms will promote the development of diagnostic assays that detect only the glycosylated form of a protein, thus increasing the specificity and lowering the false-positive rate. Structural elucidation of aberrant glycosylation by MS analysis will also provide new insights into the cellular and molecular pathology of prion diseases and lead to the identification of enzymes involved in neuropathogenesis that can be used as diagnostic markers or treatment targets.

The application of a systems biology approach based on datasets from genomic or proteomic analysis will permit discovery of pathophysiological pathways underlying interconnected patterns from seemingly irrelevant misregulated proteins, and thereby highlight the ones with higher probability of being genuine biomarkers for prion diseases.

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Table 1. Potential biomarkers of prion diseases identified by mass spectrometry-based proteomics.
Protein	Source of sample	Identification method	Prion disease	Ref.
14-3-3 protein	CSF	2D-GE	CJD	[119]
α1-antichymotrypsin	CSF	2D-GE	CJD	[50]
Apolipoprotein A1	CSF	2D-GE	CJD	[50]
Apolipoprotein A4	CSF	2D-GE	CJD	[50]
Apolipoprotein J	CSF	2D-GE	CJD	[50]
Apoliprotein E	CSF	2D-GE	CJD	[120]
Complement factor B/3a	CSF	2D-GE	CJD	[50]
Cystatin C	CSF	2D-GE, SELDI-TOF	CJD	[50,52]
Fatty acid binding protein	CSF, plasma	2D-GE	CJD	[56]
Fibrin-β	CSF	2D-GE	CJD	[50]
Fibrinogen γ chain	CSF	2D-GE	CJD	[50]
Gelsolin	CSF	2D-GE, 2D-DIGE	CJD	[50,51]
Hp2-α haptoglobin	CSF	2D-GE	CJD	[50]
Lactate dehydrogenase B chain	CSF	2D-DIGE	CJD	[51]
Neuron-specific enolase	CSF	2D-DIGE	CJD	[51]
Prostaglandin D2 synthase	CSF	2D-DE	CJD	[50]
Transferrin	CSF	2D-DE	CJD	[50]
Transthyretin	CSF, serum	2D-DIGE, SELDI-TOF	CJD, scrapie	[51,68]
Thymosin-β 4	CSF	MALDI-TOF	CJD	[53]
Ubiquitin	CSF	2D-GE, MALDI-TOF, SELDI-TOF	CJD	[50,53,121]
Serum amyloid P-component	Plasma	2D LC-MS/MS	Scrapie	[65]
Clusterin E/M	Urine	2D-DIGE	BSE	[75,78]
Ig γ-2 chain C region	Urine	2D-DIGE	BSE	[75]
Cystatin	Urine	2D-DIGE	BSE	[75]
Cathelicidin antimicrobial peptide	Urine	2D-DIGE	BSE	[75]
Uroguanylin	Urine	2-DIGE	BSE	[75]

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