**3. The Hsp70 machinery members as biomarkers of PD**

A biomarker is a naturally occurring molecule, gene, or characteristic by which a particular medical condition, disease, etc. can be identified. Despite the current relevance of identifying a biomarker for early diagnosis of PD and/or to follow up its progression, up to date there is no reliable biomarker available (Morgan et al., 2010; Nyhlen et al., 2010). Therefore, certain key proteins that are thought to be tightly linked to PD pathogenesis or progression, such as the members of the Hsp70 machinery discussed above, which could manifest changes in their expression levels in body fluids cells or alter their presence in body fluids in a PD scenario, could represent potential markers of disease development or predisposition.

Currently, it is well established the most promising biomarkers for PD in cerebrospinal fluidic (CSF) are αSyn, DJ-1, amyloid β, and the tau protein. These are the principal targets in the Parkinson's Progression Markers Initiative, a public-private, large-scale study project that aims to identify biological markers of disease progression (www.PPMI-info.org). DJ-1, which is the only chaperone to be included in this study, is a mitochondrial chaperone which has been one of the most studied proteins for its potential use as a PD biomarker. However, results published thus far from measurements of DJ-1 in CSF (Hong et al., 2010) and serum from PD patients (Hong et al., 2010; Shi et al., 2010; Waragai et al., 2007) are somewhat controversial or inconsistent, which could probably be explained by the high DJ-1 protein level present in blood cells (Shi et al., 2010)**.** 

Currently, it is well established that certain proteins, including members of the Hsp70 family such as Hsp701A and 1B, display perturbed expression levels in the SN of PD brains (Hauser et al., 2005); however, changes in tissue expression levels are in principle not useful for an application as biomarkers. Recently, a significant decrease in whole blood mRNA levels of St13/Hip co-chaperone was reported for early PD patients, but not for AD patients or healthy controls (Scherzer et al., 2007). However, a second group reported no significant differences in the expression pattern of ST13 in early-stage PD patients, as compared to controls (Shadrina et al., 2010). This discrepancy could be attributed, at least in part, to heterogeneity in the criteria of diagnosing and classifying the individuals into groups and to the difficulty in establishing the actual onset of the disease. Yet another study found differences in HSPA8 (Hsc70) and HIP2 expression levels between PD patients and controls (Grunblatt et al., 2010). Other members of the Hsp70 machinery are known to change their expression patterns in PD patients compared to healthy controls (Hauser et al., 2005)**.** Unfortunately, these changes appear not specific or sufficient to differentiate between PD and other related neurodegenerative disorders (Hauser et al., 2005). This is probably due to the fact that the Hsp70 system plays a central role in maintaining cell proteostasis, which is perturbed in a variety of neurodegenerative diseases.

Considering that PD is a complex pathology that involves several systems such as the stress response, the UPS, the immune system, etc., a unique biomarker might not be enough as a tool for diagnosis or follow-up of disease progression. Instead, there is general consensus that the use of a set of distinct parameters, such as protein expression profiles, age, symptoms and others, would probably be the best approach (Fasano et al., 2008; Grunblatt et al., 2010; Scherzer et al., 2007).

A biomarker is a naturally occurring molecule, gene, or characteristic by which a particular medical condition, disease, etc. can be identified. Despite the current relevance of identifying a biomarker for early diagnosis of PD and/or to follow up its progression, up to date there is no reliable biomarker available (Morgan et al., 2010; Nyhlen et al., 2010). Therefore, certain key proteins that are thought to be tightly linked to PD pathogenesis or progression, such as the members of the Hsp70 machinery discussed above, which could manifest changes in their expression levels in body fluids cells or alter their presence in body fluids in a PD scenario, could represent potential markers of disease development or

Currently, it is well established the most promising biomarkers for PD in cerebrospinal fluidic (CSF) are αSyn, DJ-1, amyloid β, and the tau protein. These are the principal targets in the Parkinson's Progression Markers Initiative, a public-private, large-scale study project that aims to identify biological markers of disease progression (www.PPMI-info.org). DJ-1, which is the only chaperone to be included in this study, is a mitochondrial chaperone which has been one of the most studied proteins for its potential use as a PD biomarker. However, results published thus far from measurements of DJ-1 in CSF (Hong et al., 2010) and serum from PD patients (Hong et al., 2010; Shi et al., 2010; Waragai et al., 2007) are somewhat controversial or inconsistent, which could probably be explained by the high DJ-1 protein level present in blood cells

Currently, it is well established that certain proteins, including members of the Hsp70 family such as Hsp701A and 1B, display perturbed expression levels in the SN of PD brains (Hauser et al., 2005); however, changes in tissue expression levels are in principle not useful for an application as biomarkers. Recently, a significant decrease in whole blood mRNA levels of St13/Hip co-chaperone was reported for early PD patients, but not for AD patients or healthy controls (Scherzer et al., 2007). However, a second group reported no significant differences in the expression pattern of ST13 in early-stage PD patients, as compared to controls (Shadrina et al., 2010). This discrepancy could be attributed, at least in part, to heterogeneity in the criteria of diagnosing and classifying the individuals into groups and to the difficulty in establishing the actual onset of the disease. Yet another study found differences in HSPA8 (Hsc70) and HIP2 expression levels between PD patients and controls (Grunblatt et al., 2010). Other members of the Hsp70 machinery are known to change their expression patterns in PD patients compared to healthy controls (Hauser et al., 2005)**.** Unfortunately, these changes appear not specific or sufficient to differentiate between PD and other related neurodegenerative disorders (Hauser et al., 2005). This is probably due to the fact that the Hsp70 system plays a central role in maintaining cell proteostasis, which is perturbed in a variety of neurodegenerative

Considering that PD is a complex pathology that involves several systems such as the stress response, the UPS, the immune system, etc., a unique biomarker might not be enough as a tool for diagnosis or follow-up of disease progression. Instead, there is general consensus that the use of a set of distinct parameters, such as protein expression profiles, age, symptoms and others, would probably be the best approach (Fasano et al., 2008; Grunblatt

**3. The Hsp70 machinery members as biomarkers of PD** 

predisposition.

(Shi et al., 2010)**.** 

diseases.

et al., 2010; Scherzer et al., 2007).
