Proteomic analysis of prion diseases: Creating clarity or causing confusion?

Abstract

Prion diseases, or transmissible spongiform encephalopathies, are progressive, fatal neurodegenerative diseases. There are both human and animal forms of the disease and all are associated with the conversion of a normal host-coded cellular prion protein (PrP(C) ) into an abnormal protease-resistant isoform (PrP(Sc) ). Although methodologies are sensitive and specific for postmortem disease diagnosis, the use of PrP(Sc) as a preclinical or general biomarker for surveillance is difficult, due to the fact that it is present in extremely small amounts in accessible tissues or body fluids such as blood, urine, saliva, and cerebrospinal fluid. Recently, amplification techniques have been developed, which have enabled increased sensitivity for PrP(Sc) detection. However, it has recently been reported that proteinase K sensitive, pathological isoforms of PrP may have a significant role in the pathogenesis of some prion diseases. Accordingly, the development of new diagnostic tests that do not rely on PrP(Sc) and proteinase K digestion is desirable. The search for biomarkers (other than PrP(Sc) ) as tools for diagnosis of prion diseases has a long history. Ideally biomarkers able to detect all transmissible spongiform encephalopathies, even at preclinical stages of infection are desirable but not yet possible due to the heterogeneity of the disease and lengthy disease progression. Recent advances in neuroproteomics have led to an overwhelming amount of information, which may offer insight on protein-protein interactions. While the amount of data obtained is impressive, the ability to relate it to the disease and validating its usefulness in diagnostic biomarker development remains a formidable challenge.

NCAM1 Polysialylation

“…Several excellent reviews on protein–protein interactions that PrP C (Watts and Westaway, 2007; Aguzzi et al, 2008; Rubenstein, 2012) or NCAM1 (Nielsen et al, 2010) engage in have been published before. Here, the scope will be limited to describing evidence in support of an interaction between PrP C and NCAM1.…”

Proteomics Approach to Identify Biomarkers in Neurodegenerative Diseases

“…Some of the downregulated proteins include those involved in the actin cytoskeleton assembly and retrograde transport from early and late endosomes to the trans-Golgi network (Shi et al, 2015). Animal studies have shown that prion disease-regulated genes could be found in gene families associated with lysosome organization/biogenesis, immune cell activation/inflammatory response, lipid metabolism, apoptosis, protein biosynthesis/proteolysis, nervous system function/synaptic transmission, and cytoskeleton organization/biogenesis (Rubenstein, 2012). Most of the upregulated genes were associated with proliferation and activation of astrocytes and microglia such as inflammation, cellular movement, lipid metabolism, and lysosomal activity, while the majority of downregulated genes were associated with neuronal and synaptic dysfunction leading to neuronal cell death (Rubenstein, 2012).…”

“…Animal studies have shown that prion disease-regulated genes could be found in gene families associated with lysosome organization/biogenesis, immune cell activation/inflammatory response, lipid metabolism, apoptosis, protein biosynthesis/proteolysis, nervous system function/synaptic transmission, and cytoskeleton organization/biogenesis (Rubenstein, 2012). Most of the upregulated genes were associated with proliferation and activation of astrocytes and microglia such as inflammation, cellular movement, lipid metabolism, and lysosomal activity, while the majority of downregulated genes were associated with neuronal and synaptic dysfunction leading to neuronal cell death (Rubenstein, 2012). Interestingly, in human studies, there was no increase of PrP in either the cortex or the cerebellum of the patients; on the contrary, there was a decrease of PrP compared to the normal brains.…”

“…However, the marker is not very reliable as several false-negative and false-positive results have also been reported in sporadic CJD patients (Chapman, McKeel, & Morris, 2000;Green, Knight, Macleod, Lowman, & Will, 2001). Other proteins that are used as diagnostic markers alongside the 14-3-3 protein are β-amyloid, tau-protein, and phosphorylated isoforms, S100b, as well as neuron-specific enolase (Rubenstein, 2012). However, as with the 14-3-3, these proteins are not prion disease specific and are found to be differentially regulated in other neurodegenerative diseases as well.…”

An emerging role of the cellular prion protein as a modulator of a morphogenetic program underlying epithelial-to-mesenchymal transition

“…Although there are divergent views regarding the significance of protein–protein interactions of PrP C (Watts and Westaway, 2007 ; Aguzzi et al, 2008 ; Rubenstein, 2012 ), there appears to be a broad consensus that PrP C exerts some of its biological role through its affiliation with caveolae and specialized membrane domains referred to as lipid rafts (Naslavsky et al, 1997 ; Mouillet-Richard et al, 2000 ). Furthermore, there is agreement that the molecular microenvironment of PrP C in neurons is dominated by cell adhesion molecules that include neural cell adhesion molecule (NCAM) (Walsh et al, 1989 ), L1, integrins and non-integrin laminin receptors known to modulate cell-to-substrate contacts (Gauczynski et al, 2001 ; Watts et al, 2009 ).…”