SCIENTIFIC CONSULTANTS RESEARCHERSSCIENTIFIC CONSOLTANTS RESEARCHERS FOR FREE PROPOSAL

doi:10.1016/j.neuroscience.2010.06.057 | How to Cite or Link Using DOI Copyright © 2010 IBRO Published by Elsevier Ltd.

Permissions & Reprints

Granins as disease-biomarkers: Translational potential for psychiatric and neurological disorders

A. Bartolomucci^{a, 1, ,} , G.M. Pasinetti^b and S.R.J. Salton^{c, ,}

^a Department of Evolutionary and Functional Biology, University of Parma, 43124 Parma, Italy
^b Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA
^c Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA

Accepted 23 June 2010. 

Available online 1 July 2010.

Abstract

The identification of biomarkers represents a fundamental medical advance that can lead to an improved understanding of disease pathogenesis, and holds the potential to define surrogate diagnostic and prognostic endpoints. Because of the inherent difficulties in assessing brain function in patients and objectively identifying neurological and cognitive/emotional symptoms, future application of biomarkers to neurological and psychiatric disorders is extremely desirable. This article discusses the biomarker potential of the granin family, a group of acidic proteins present in the secretory granules of a wide variety of endocrine, neuronal and neuroendocrine cells: chromogranin A (CgA), CgB, Secretogranin II (SgII), SgIII, HISL-19 antigen, 7B2, NESP55, VGF and ProSAAS. Their relative abundance, functional significance, and secretion into the cerebrospinal fluid (CSF), saliva, and the general circulation have made granins tractable targets as biomarkers for many diseases of neuronal and endocrine origin, recently impacting diagnosis of a number of neurological and psychiatric disorders including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia, and schizophrenia. Although research has not yet validated the clinical utility of granins as surrogate endpoints for the progression or treatment of neurological or psychiatric disease, a growing body of experimental evidence indicates that the use of granins as biomarkers might be of great potential clinical interest. Advances that further elucidate the mechanism(s) of action of granins, coupled with improvements in biomarker technology and direct clinical application, should increase the translational effectiveness of this family of proteins in disease diagnosis and drug discovery.

Key words: •••

Abbreviations: ALS, amyotrophic lateral sclerosis; CgA, chromogranin A; CgB, chromogranin B; CSF, cerebrospinal fluid; MS, multiple sclerosis; SgII, secretogranin II

Article Outline

Clinical, relevance of disease biomarkers

The granin family

Granins as biomarkers for neurological and psychiatric disorders

Amyotrophic lateral sclerosis

Multiple sclerosis

Alzheimer's disease, pick's disease and frontotemporal dementia

Schizophrenia

Future of granins as diagnostic tools and targets in drug discovery and development

References

Clinical, relevance of disease biomarkers

Biological markers (also called biomarkers) are characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to therapeutic intervention. The identification of biomarkers represents a fundamental advance in medicine that may lead to improved understanding of disease pathogenesis and holds the potential to define surrogate diagnostic and prognostic endpoints (Biomarkers Definitions Working Group, 2001). The requirements for a useful disease biomarker are that its level can be unambiguously determined with high reproducibility and that its presence (or level) could distinguish ill from healthy persons. Classical examples include the use of increased blood glucose levels to make a diagnosis of diabetes while their decline identifies treatment efficacy. Biomarkers could be of great potential utility for neurological and psychiatric disorders because of inherent difficulties assessing brain function and structure in patients and objectively identifying neurological and cognitive/emotional symptoms. The utility of the biomarker approach is well described for Alzheimer's disease. Its key diagnostic markers, that is the presence of plaques of aggregated beta-amyloid and hyperphosphorylated tau proteins, can only be retrospectively assessed in post-mortem brain. Indeed, an ongoing program showed the diagnostic utility of altered truncated β-amyloid or tau in the cerebrospinal fluid (CSF) or plasma (Blennow et al., 2006).

The granin family

The granin family includes chromogranins, secretogranins and additional related acidic proteins, sharing phylogenetically well-conserved domains within the primary structure ([Benedum et al., 1987] and [Eiden, 1987]), which are present in the secretory granules of a wide variety of endocrine, neuronal and neuroendocrine cells: Chromogranin A (CgA), Chromogranin B (CgB), Secretogranin II (SgII), Secretogranin III (SgIII), HISL-19 antigen (SgIV), 7B2 (SgV), NESP55 (SgVI), VGF (SgVII) and ProSAAS (SgVIII)¹. The chromogranin and secretogranin proteins share many properties, including acidic pI, binding to calcium, the presence of multiple dibasic cleavage sites, and the propensity to form aggregates, that are summarized in Table 1 and several excellent reviews ([Helle, 2004] and [Taupenot et al., 2003]). Granins are ubiquitous in secretory cells of the nervous, endocrine and immune systems, where they regulate a number of cellular functions including protein sorting, granulogenesis, and prohormone convertase (PC) activity, as well as preventing uncontrolled osmotic swelling of secretory vesicles that contain 1500 mOsm of cargo (for review [Taupenot et al., 2003] and [Helle, 2004]). Below we will provide a short summary of CgA, CgB, SgII and VGF. The reader is referred to excellent recent reviews covering the biological, cellular and molecular properties of the entire family of proteins ([Huttner et al., 1991], [Taupenot et al., 2003] and [Helle, 2004]).

Table 1. Structural characteristics of granin family proteins

Granin protein	Amino acids (mature human protein)	Mr calc (kDa)	pIcalc/pImeas	Paired basic amino acids
CgA	439	49,156	4.45/4.9h	9
CgB	657	76,329	4.83/5.2h	16
SgII	587	67,752	4.48/5.0b	9
SgIII	449	50,989	4.75/5.1m	6
7B2 (SgV)	186 (i-1)	20,788	6.06/5.0p	4
	185 (i-2)	20,717
NESP55 (SgVI)	245	28,827	5.22/5.0b	9
VGF (SgVII)	593	64,996	4.53/ND	10
pro-SAAS (SgVIII)	227	24,033	5.46/ND	6

Sequences of mature human granin family proteins, obtained from the NCBI and Swiss protein databases, were analyzed using MacVector. Molecular weight (Mr), isoelectric point (pIcalc), number of paired basic amino acid residues that are potential proprotein convertase cleavage sites, and amino acid number, were determined. Experimentally-obtained pI values were previously referenced (Helle, 2004), for human (h), bovine (b), murine (m), and porcine (p) granin proteins.

CgA was the first granin to be isolated and was characterized as an acidic protein co-stored and co-released with the catecholamine hormones from the bovine adrenal medulla (Banks and Helle, 1965). CgB was first identified as a tyrosine-sulfated protein from rat PC12 cells, and was later renamed after being detected as a conspicuous component of the bovine adrenal medulla (Eiden et al., 1987). Although CgA and CgB are products of different genes, analyses of their primary structure and gene organization have revealed a closer relationship between these two genes/proteins. CgA and CgB are considered granulogenic proteins that play a prominent role in dense-core granule biogenesis and as chaperones for sorting to the regulated secretory pathway in endocrine cells ([Courel et al., 2006] and [Koshimizu et al., 2010]). Both CgA and CgB are also considered prohormones. In the trans-Golgi network and secretory granule, they aggregate in the presence of calcium and decreasing pH. Within the granule, a fraction of CgA and CgB is processed to bioactive peptides, including Vasostatin I and II, pancreastatin, cestatin and serpin for CgA and CgB1–41 and secretolytin for CgB (reviewed in [Taupenot et al., 2003] and [Helle, 2004]). The best characterized receptor-mediated effect for the entire granin family is the association of the CgA-peptide catestatin with the nicotinic cholinergic receptor. Upon co-release of catestatin with norepinephrine, catestatin inhibits nicotinic cholinergic receptor responses, thereby exerting a negative feedback on catecholamine release (Mahata et al., 1997).
SgII was initially discovered in the bovine anterior pituitary (Rosa and Zanini, 1981) and investigated as a model protein to characterize mechanisms involving biogenesis of large dense core vesicles and sorting of secretory proteins to the regulated pathway (Fischer-Colbrie et al., 1995). The widespread distribution of SgII throughout the endocrine and nervous system is comparable and overlapping to that of CgA and CgB (Winkler and Fischer-Colbrie, 1992). Upon processing by PCs, SgII releases several bioactive peptides including secretoneurin (Kirchmair et al., 1993) and manserin (Yajima et al., 2004).
The Vgf gene, originally identified as a nerve growth factor responsive gene (Levi et al., 1985), has a tissue-specific pattern of expression limited to neurons within the central and peripheral nervous systems and to various endocrine cells ([Salton et al., 1991], [Salton et al., 2000], [Snyder and Salton, 1998] and [Ferri and Possenti, 1996]). The VGF gene encodes a 617 amino acid protein in rodents (615 in humans) that is stored in dense core granules and processed to yield a number of peptides ([Salton et al., 1991], [Trani et al., 1995], [Ferri and Possenti, 1996] and [Levi et al., 2004]). More than 10 different VGF-derived peptides have been detected to date, exerting a variety of functions including regulation of energy balance, pain modulation, sexual behaviour and gut contraction (e.g. [Bartolomucci et al., 2006], [Bartolomucci et al., 2007], [Yamaguchi et al., 2007] and [Severini et al., 2009]. For reviews, [Levi et al., 2004] and [Toshinai and Nakazato, 2009]).
Overall, diverse biological activities of specific granin-derived peptides have been identified, including pro-hormone convertase inhibition, regulation of pro-hormone convertase folding/sorting, hormone and neurotransmitter release (insulin, PTH, vasopressin, catecholamines), neuronal excitability, and smooth muscle and vascular contractility. As a consequence, granin-derived peptides have been investigated in several pathological contexts including in neurological, neoplastic, metabolic and mood disorders (Taupenot et al., 2003). More recently, their relative abundance, functional significance, and secretion into the CSF, saliva, and the general circulation have made granin peptides tractable targets as biomarkers for many diseases of neuronal and endocrine origin.

Granins as biomarkers for neurological and psychiatric disorders

The potential utility of granins as biomarkers of neurological and psychiatric disorders has only recently been established, impacting amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia, and schizophrenia. The earliest proteomic studies mainly focused on CgA, while recent data address a prominent role for CgB, SgII and VGF (see [Fig. 1] and [Fig. 2]). Because of the relative novelty of this field, a cautionary note should be raised to highlight that most of the studies reviewed here, with a few notable exceptions, have relatively small sample sizes, and the differences measured in granin protein or granin peptide fragment levels between patients and controls is often small. Perhaps as a consequence, many results have not always been confirmed in follow-up studies.

Full-size image (67K) High-quality image (433K)

Fig. 1. Chromogranin A (CgA), chromogranin B (CgB), and secretogranin II (SgII) as disease biomarkers. A subset of peptides cleaved from CgA, CgB, and SgII are indicated by the red rectangles below each mature human granin protein. Biomarker peptide fragments isolated from CSF (green rectangles) and antibodies made to granin peptides or fragments (green elipses), shown above the granin proteins, were used to characterize the following diseases: Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS), Frontal Temporal Dementia (FTD), Multiple Sclerosis (MS), Pick's Disease, and Schizophrenia (SCZ). For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.

Full-size image (76K) High-quality image (613K)

Fig. 2. VGF-derived peptides/fragments associated with disease in humans or in animal models. VGF fragments (in green) are increasingly recognized as disease biomarkers in humans, while several biologically active peptides (in red) have been identified in rats/mice. Peptides are indicated according to nomenclature indicated in Table 2. Protein sequences can be found at http://www.ncbi.nlm.nih.gov/protein. For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a form of progressive, fatal, neurodegenerative disease caused by the degeneration of motor neurons, occurring in familial (less that 10%) or sporadic forms. The etiology remains unclear, although a mutation in the gene encoding SOD1 has been observed in 20% of familial cases (Rosen et al., 1993). More recently gene-association studies have established an array of new candidate loci which might elucidate the pathogenesis of this devastating neurological disorder (e.g. [Greenway et al., 2006], [Sreedharan et al., 2008] and [Maruyama et al., 2010]).
A mutant variant (P413L) in the CgB gene of ALS patients has recently been identified (Gros-Louis et al., 2009). The P413L mutation was present in 10% of ALS patients (n=751, including both sporadic and familial forms of ALS) as compared to 4.5% in healthy individuals (n=705). In particular, individuals carriers of the P413L gene variant in a sample of French/French-Canadian origin (n=289) showed a higher prevalence of the mutation (17%) and relative 3.3-fold higher risk to develop ALS. In a cross-validation study in a Swedish population, although the P413L mutation showed a lower prevalence (5.2%), it still conferred a 1.5 fold higher relative risk to develop ALS. Interestingly, the P413L mutation lowered age at disease onset from 62 to 55 years in sporadic ALS, and from 55 to 43 years in familial ALS patients (Gros-Louis et al., 2009). It is predicted that the P413L variant may affect protein structure but the biological mechanism responsible for the higher risk to develop ALS has not been identified so far. However, the same research group also recently demonstrated in vitro and in vivo in mouse models of ALS, that CgA and CgB interact with and determine the secretion of mutant but not wild-type SOD1 protein which, in turn, may trigger microgliosis and neuronal death (Urushitani et al., 2006).
Earlier immunohistochemical studies identified an aberrant CgA pattern in ALS patients ([Schiffer et al., 1995] and [Yasuhara et al., 1994]). These findings were recently replicated and extended to identify lower CgA (−44%), CgB (−27%) and SgII (−44%) levels and an association with SOD1-positive intracellular aggregates in motor neurons of a relatively small sample (n=8) of ALS patients when compared with controls (Schrott-Fischer et al., 2009). In addition, salivary CgA is increased by 300% in terminal ALS patients (n=12) when compared to healthy individuals (n=26), with a minimum overlap between the two groups (Obayashi et al., 2008). Salivary CgA was also positively correlated with emotional functioning (Obayashi et al., 2008). In addition to CgA and CgB, another granin, VGF, has recently been identified as a diagnostic biomarker in ALS patients (Pasinetti et al., 2006). Indeed three proteins were found in lower concentrations in the CSF of ALS patients (n=36) when compared to healthy individuals (n=21). One of these was the fragment VGF_398–411² (−32.8%), the second was cystatin C (−48%) while the third (−32.2%) remained unidentified. The changes were confirmed in an independent although smaller cohort of ALS patients and healthy controls. The levels of these three proteins provided 95% accuracy, 91% sensitivity and 97% specificity for diagnosing ALS. If the VGF_398–411 fragment was considered alone, these levels generally decreased, but accuracy (72%) and specificity (86%) remained in a good range, while accuracy significantly dropped to 48%. The functional role of the VGF_398–411 fragment remains to be determined but it is of interest that it maps to a region of the protein between two clusters of biologically active peptides identified so far only in rodents (Fig. 2). The same research group recently demonstrated that the decrease in CSF VGF (entire propeptide) progressed with the clinical severity of ALS in both humans (a small cohort of ALS, n=17, and normal, n=21, subjects) and a mouse model (Zhao et al., 2008). In the mouse model, the decrease of the VGF protein preceded onset of clinical symptoms. Furthermore overexpression of full length VGF in a cellular model of ALS protected spinal cord neurons against excitotoxic injury (Zhao et al., 2008).
In conclusion, genetic and proteomic studies suggest both a potential role for granins in ALS and future clinical applications of granin biomarkers.

Table 2. VGF-derived peptides/fragments associated with disease in humans or in animal models

Disease	Peptide/fragment aa residue (species)	Effect	Stage	Reference
Neurological disease
Alzheimer's disease	378–397 (human)	Decreased in patient's CSF	Identified as potential biomarker	Carrette et al., 2003
	Fragment not specified (human)	Decreased in patient's CSF	Identified as potential biomarker	Simonsen et al., 2007
Amyotrophic lateral sclerosis	398–411 (human) Entire pro-peptide (human)	Decreased in patient's CSF	Identified as potential biomarker	Pasinetti et al., 2006
	Entire pro-peptide (mouse)	Decreased in CSF, serum and motor neurons	Pre-clinical	Zhao et al., 2008
Frontotemporal dementia	26–62 (human)	Decreased in patient's CSF	Identified as potential biomarker	Rüetschi et al., 2005
Pain	TLQP-21 556–576 (mouse)	Hyperalgesia (peripheral) analgesia (icv)	Pre-clinical	Rizzi et al., 2008
	TLQP-62 556–617 (mouse, rat)	Allodynia	Pre-clinical	Moss et al., 2008
	AQEE-30 588–617 (mouse, rat)	Hyperalgesia	Pre-clinical	Riedl et al., 2009
	LQEQ-19 598–617 (mouse, rat)	Hyperalgesia	Pre-clinical	Riedl et al., 2009
Psychiatric disease
Schizophrenia/depression	23–62 (human)	Increased in patient's CSF	Identified as potential biomarker	[Huang et al., 2006] and [Huang et al., 2007]
Depression	TLQP-62,556–617 (mouse, rat)	Antidepressant-like effect	Pre-clinical	Thakker-Varia et al., 2007
Depression/anxiety	AQEE-30 588–617 (mouse, rat)	Antidepressant- and anxiolytic-like effects	Pre-clinical	Hunsberger et al., 2007
Other disease
Obesity/eating disorders	TLQP-21 556–576 (mouse, hamster)	Limits diet induced obesity (mice, hamster) anorexia (hamster)	Pre-clinical	Bartolomucci et al., 2006
	NERP2 313–350 (rat)	Enhance food intake in an orexin-dependent manner	Pre-clinical	Toshinai et al., in press
	TLQP-62 and HHPD-41 55–617 and 577–617 (mouse)	Enhanced food intake	Pre-clinical	Unpublished, referred to by Bartolomucci et al., 2007

Full-size table

A growing body of clinical and preclinical evidence links VGF-derived peptides in preclinical models and VGF-fragments in human with depression, anxiety, neuropathic and inflammatory pain, and obesity.

Multiple sclerosis

Multiple sclerosis (MS) is a complex neurological disease characterized by a combination of inflammation, demyelination and axonal damage. Mattsson and colleagues (2007) identified decreased level of CgB_306–365 (−16%) and CgB_441–493 (−16%) fragments and of the SgII peptide secretoneurin (−15%) in the CSF of MS patients (n=46) compared to healthy siblings (n=46) and non-related controls (n=50). In contrast, the CgA_194–213 fragment was increased in the CSF of MS patients when compared to patients suffering from other neurological diseases that lack an inflammatory component ([Stoop et al., 2008] and [Stoop et al., 2009]). Although healthy controls were not included in the latter study, it is of potential clinical relevance that CgA could not differentiate between MS patients and patients suffering from other inflammatory neurological diseases, which may imply that CgA is also a marker of non-specific inflammation (Stoop et al., 2008). Finally, Stoop and coworkers (2009) also report that another granin, the 7B2_125–142 fragment, was increased in patients affected by neurological disease of inflammatory origin compared to clinically isolated syndromes of demyelination.

Alzheimer's disease, pick's disease and frontotemporal dementia

Alzheimer's disease, Pick's disease and frontotemporal dementia are neurodegenerative disorders characterized by different pathogenic mechanisms which encompass aggregates of straight filaments composed of hyperphosphorylated tau proteins or other proteins such as amyloid beta. Collectively these pathologies can be referred to as tauopathies (Lee et al., 2001). In addition to neurological, psychiatric and clinical diagnoses, altered levels of tau and amyloid fragments in CSF are routinely used for diagnostic purposes, although their diagnostic performance is not optimal with regard to specificity ([Blennow et al., 2006] and [Sonnen et al., 2008]). Several studies identified increased CgA, SgII and ProSAAS, in post-mortem filament aggregates in tauopathies ([Weiler et al., 1990], [Munoz, 1991], [Kikuchi et al., 2003], [Wada et al., 2004] and [Lechner et al., 2004]), and one proteomic study identified a decreased CgA level in the CSF of canonical but not late onset Type II (Kamboh, 2004) Alzheimer's disease patients (Blennow et al., 1995, but see O'Connor et al., 1993). More recently, several proteomic studies have confirmed the potential utility of granin fragments as candidate diagnostic biomarkers for tauopathies. Simonsen et al. (2007) reported a decreased level of CgA peptide vasostatin II, and a decrease in a non specified fragment of the VGF propeptide in a cohort (n=85) of AD patients compared to patients suffering from frontotemporal dementia (n=20) and healthy controls (n=32). The VGF_378–397 fragment was slightly but significantly decreased (30% decrease but with a large variance) in the CSF of a small sample (n=9) of Alzheimer's patients (Carrette et al., 2003). Three different granins, that is ProSAAS (Davidsson et al., 2002), VGF_26–62 and CgB_446–493 fragments (Rüetschi et al., 2005), were found to be decreased in the CSF of patients affected by frontotemporal dementia. In particular Rüetschi and coworkers (2005) showed in a small sample of frontotemporal patients (n=16) that the combination of VGF_26–62, CgB_446–493, plus two additional biomarkers allowed discrimination from controls with a sensitivity of 94%, a specificity of 83%, and an accuracy of 89%.

Schizophrenia

Schizophrenia is a neuropsychiatric disorder characterized by abnormalities in the perception or expression of reality, often manifested by auditory hallucinations and paranoid delusions. Schizophrenia is so far the only psychiatric disease for which granins have been established as candidate genes for susceptibility ([Kitao et al., 2000], [Iijima et al., 2004] and [Takahashi et al., 2006]) and consistently investigated as potential disease biomarkers. Earlier studies showed no major change in CSF CgA, CgB and SgII content ([van Kammen et al., 1991], [Landén et al., 1999a] and [Miller et al., 1996]). At variance, Miller et al. (1996) demonstrated a significant increase in CgA/secretoneurin ratio; van Kammen et al. (1991) described a negative correlation between CgA, negative symptoms and ventricle–brain ratio in schizophrenic patient; Landén et al. (1999b) showed a reduction of CgA, CgB but not SgII in the CSF of schizophrenic patients; a post mortem investigation showed lower CgB-immunoreactivity in several subregions of the hippocampus (Nowakowski et al., 2002). Overall, published studies are inconsistent in their support of an association between CgA, CgB or SgII and schizophrenia. In contrast, increased CSF content of VGF_23–62 fragment was recently reported in first onset drug naive schizophrenic patients (Huang et al., 2006). This important study having a relatively large sample size (n=58 schizophrenic and n=90 controls), cross validation groups (n=17 schizophrenic and n=40 controls) and disease specificity analysis (depression, obsessive-compulsive disorder and Alzheimer's disease) showed a sensitivity of 88% and a specificity of 95% for schizophrenia. In addition: (1) VGF_23–62 was consistently increased in two independent groups of schizophrenic patients (40%); (2) the increase was confirmed in a small group (n=5) of post mortem brains by western blot; (3) VGF_23–62 was also increased in a small group of depressed patients (n=16), but not in obsessive compulsive disorder (n=5) or Alzheimer's patients (n=10), suggesting that it could be associated with underlying mechanisms of both schizophrenia and depression, and that the diagnosis of schizophrenia would require an association of several disease biomarkers; (4) the VGF_26–62 fragment (truncated by three N-terminal aa when compared to the 23–62 peptide) was identified in the CSF, but did not discriminate between schizophrenic and normal patients. Interestingly the VGF_26–62 fragment is decreased in frontotemporal dementia patients (see above, Rüetschi et al. (2005)). A later report by the same group showed a similar increase in VGF_23-62 fragment in a set of patients prodromal for psychosis (n=24), a fraction (29%) of which became schizophrenic during the 3 years follow up (Huang et al., 2007).
In conclusion, proteomic studies showed that CgA, CgB and SgII did not strongly associate with schizophrenia while a VGF fragment was increased when compared to healthy controls and could be considered a reliable biomarker for future validating studies and in a larger sample of schizophrenic patients.

Future of granins as diagnostic tools and targets in drug discovery and development

Although research has not yet validated the clinical utility of granins as surrogate endpoints for neurological or psychiatric disease, a growing body of experimental evidence strongly suggests that granin biomarkers might soon stimulate more widespread clinical interest. While the majority of proteomic studies with potential clinical relevance have thus far investigated the classical granin proteins CgA and CgB, VGF is emerging as a key potential diagnostic biomarker in a number of neurological and psychiatric diseases.
Forty-five years after the identification of the first granin protein, CgA, the widespread utility of granins as disease biomarkers has been established for neuroendocrine tumors ([Conlon , in press] and [Harsha et al., 2009]). Concurrently, CgA-derived peptides are in an advanced stage of development as diagnostic biomarkers for cardiovascular disease and essential hypertension ([Sahu et al., 2010] and [Helle, 2010]). A patent watch (performed using http://v3.espacenet.com/) returned two patents on CgA relevant to the present discussion. Patent WO2008085035, filed by the University Erasmus Medical Center of Utrecht, The Netherlands, describes the diagnostic utility of CgA as a biomarker in multiple sclerosis. Similarly, the Beijing Chemclin Biotech Company Ltd. has filed a patent describing a CgA chemiluminescent quantitative detection kit with potential applications in the clinic (CN101377513). The utility of granin biomarkers as diagnostic tools for life threatening and widespread neurological and psychiatric disease necessitates their objective validation by larger scale testing, and in many cases is dependent on the development and application of specific immunological reagents and protein/peptide analytical techniques. Advances that further elucidate the mechanism(s) of action of granins and granin-derived peptides, coupled with improvements in biomarker technology and direct clinical application, should broaden the future utility of this family of proteins in disease diagnosis and drug discovery.

References

Banks and Helle, 1965 P. Banks and K.B. Helle, The release of protein from the stimulated adrenal medulla, Biochem J 97 (1965), pp. 40C–41C.

Bartolomucci et al., 2006 A. Bartolomucci, G. La Corte, R. Possenti, V. Locatelli, A.E. Rigamonti, A. Torsello, E. Bresciani, I. Bulgarelli, R. Rizzi, F. Pavone, F.R. D'Amato, C. Severini, G. Mignogna, A. Giorgi, M.E. Schininà, G. Elia, C. Brancia, G.L. Ferri, R. Conti, B. Ciani, T. Pascucci, G. Dell'Omo, E.E. Muller, A. Levi and A. Moles, TLQP-21, a VGF-derived peptide, increases energy expenditure and prevents the early phase of diet-induced obesity, Proc Natl Acad Sci U S A 103 (2006), pp. 14584–14589. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (23)

Bartolomucci et al., 2007 A. Bartolomucci, R. Possenti, A. Levi, F. Pavone and A. Moles, The role of the vgf gene and VGF-derived peptides in nutrition and metabolism, Genes Nutr 2 (2007), pp. 169–180. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (4)

Benedum et al., 1987 U.M. Benedum, A. Lamouroux, D.S. Konecki, P. Rosa, A. Hille, P.A. Baeuerle, R. Frank, F. Lottspeich, J. Mallet and W.B. Huttner, The primary structure of human secretogranin: I (chromogranin B): comparison with chromogranin A reveals homologous terminal domains and a large intervening variable region, EMBO J 6 (1987), pp. 1203–1211. View Record in Scopus | Cited By in Scopus (69)

Biomarkers Definitions Working Group, 2001 Biomarkers Definitions Working Group, Biomarkers and surrogate endpoints: preferred definitions and conceptual framework, Clin Pharmacol Ther 69 (2001), pp. 89–95.

Blennow et al., 1995 K. Blennow, P. Davidsson, A. Wallin and R. Ekman, Chromogranin A in cerebrospinal fluid: a biochemical marker for synaptic degeneration in Alzheimer's disease?, Dementia 6 (1995), pp. 306–311. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (18)

Blennow et al., 2006 K. Blennow, M.J. de Leon and H. Zetterberg, Alzheimer's disease, Lancet 368 (2006), pp. 387–403. Article | PDF (2112 K) | View Record in Scopus | Cited By in Scopus (429)

Carrette et al., 2003 O. Carrette, I. Demalte, A. Scherl, O. Yalkinoglu, G. Corthals, P. Burkhard, D.F. Hochstrasser and J.C. Sanchez, A panel of cerebrospinal fluid potential biomarkers for the diagnosis of Alzheimer's disease, Proteomics 3 (2003), pp. 1486–1494. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (167)

Conlon , in press Conlon JM (in press) Granin-derived peptides as diagnostic and prognostic markers for endocrine tumors. Regul Pept.

Courel et al., 2006 M. Courel, C. Rodemer, S.T. Nguyen, A. Pance, A.P. Jackson, D.T. O'Connor and L. Taupenot, Secretory granule biogenesis in sympathoadrenal cells: identification of a granulogenic determinant in the secretory prohormone chromogranin A, J Biol Chem 281 (2006), pp. 38038–38051. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (15)

Davidsson et al., 2002 P. Davidsson, M. Sjögren, N. Andreasen, M. Lindbjer, C.L. Nilsson, A. Westman-Brinkmalm and K. Blennow, Studies of the pathophysiological mechanisms in frontotemporal dementia by proteome analysis of CSF proteins, Brain Res Mol Brain Res 109 (2002), pp. 128–133. Article | PDF (190 K) | View Record in Scopus | Cited By in Scopus (50)

Eiden, 1987 L. Eiden, Is chromogranin A a prohormone?, Nature 325 (1987), p. 301. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (31)

Eiden et al., 1987 L.E. Eiden, W.B. Huttner, J. Mallet, D.T. O'Connor, H. Winkler and A. Zanini, A nomenclature proposal for the chromogranin/secretogranin proteins, Neuroscience 21 (1987), pp. 1019–1021. Abstract | PDF (258 K) | View Record in Scopus | Cited By in Scopus (19)

Ferri and Possenti, 1996 G.L. Ferri and R. Possenti, vgf A neurotrophin-inducible gene expressed in neuroendocrine tissues, Trends Endocrinol Metab 7 (1996), pp. 233–239. Article | PDF (1193 K) | View Record in Scopus | Cited By in Scopus (9)

Fischer-Colbrie et al., 1995 R. Fischer-Colbrie, A. Laslop and R. Kirchmair, Secretogranin: II: molecular properties, regulation of biosynthesis and processing to the neuropeptide secretoneurin, Prog Neurobiol 46 (1995), pp. 49–70. Article | PDF (2043 K) | View Record in Scopus | Cited By in Scopus (143)

Greenway et al., 2006 M.J. Greenway, P.M. Andersen, C. Russ, S. Ennis, S. Cashman, C. Donaghy, V. Patterson, R. Swingler, D. Kieran, J. Prehn, K.E. Morrison, A. Green, K.R. Acharya, R.H. Brown Jr and O. Hardiman, ANG mutations segregate with familial and “sporadic” amyotrophic lateral sclerosis, Nat Genet 38 (2006), pp. 411–413. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (133)

Gros-Louis et al., 2009 F. Gros-Louis, P.M. Andersen, N. Dupre, M. Urushitani, P. Dion, F. Souchon, M. D'Amour, W. Camu, V. Meininger, J.P. Bouchard, G.A. Rouleau and J.P. Julien, Chromogranin B P413L variant as risk factor and modifier of disease onset for amyotrophic lateral sclerosis, Proc Natl Acad Sci U S A 106 (2009), pp. 21777–21782. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (3)

Harsha et al., 2009 H.C. Harsha, K. Kandasamy, P. Ranganathan, S. Rani, S. Ramabadran, S. Gollapudi, L. Balakrishnan, S.B. Dwivedi, D. Telikicherla, L.D. Selvan, R. Goel, S. Mathivanan, A. Marimuthu, M. Kashyap, R.F. Vizza, R.J. Mayer, J.A. Decaprio, S. Srivastava, S.M. Hanash, R.H. Hruban and A. Pandey, A compendium of potential biomarkers of pancreatic cancer, PLoS Med 6 (2009), p. e1000046. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (6)

Helle, 2004 K.B. Helle, The granin family of uniquely acidic proteins of the diffuse neuroendocrine system: comparative and functional aspects, Biol Rev 79 (2004), pp. 769–794. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (47)

Helle, 2010 K.B. Helle, The chromogranin A-derived peptides vasostatin-I and catestatin as regulatory peptides for cardiovascular functions, Cardiovasc Res 85 (2010), pp. 9–16. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (1)

Huang et al., 2006 J.T. Huang, F.M. Leweke, D. Oxley, L. Wang, N. Harris, D. Koethe, C.W. Gerth, B.M. Nolden, S. Gross, D. Schreiber, B. Reed and S. Bahn, Disease biomarkers in cerebrospinal fluid of patients with first-onset psychosis, PLoS Med 3 (2006), p. e428. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (0)

Huang et al., 2007 J.T. Huang, F.M. Leweke, T.M. Tsang, D. Koethe, L. Kranaster, C.W. Gerth, S. Gross, D. Schreiber, S. Ruhrmann, F. Schultze-Lutter, J. Klosterkötter, E. Holmes and S. Bahn, CSF metabolic and proteomic profiles in patients prodromal for psychosis, PLoS One 2 (2007), p. e756. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (16)

Hunsberger et al., 2007 J.G. Hunsberger, S.S. Newton, A.H. Bennett, C.H. Duman, D.S. Russell, S.R. Salton and R.S. Duman, Antidepressant actions of the exercise-regulated gene VGF, Nat Med 13 (2007), pp. 1476–1482. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (32)

Huttner et al., 1991 W.B. Huttner, H.H. Gerdes and P. Rosa, The granin (chromogranin/secretogranin) family, Trends Biochem Sci 16 (1991), pp. 27–30. Abstract | PDF (546 K) | View Record in Scopus | Cited By in Scopus (264)

Iijima et al., 2004 Y. Iijima, T. Inada, T. Ohtsuki, H. Senoo, M. Nakatani and T. Arinami, Association between chromogranin b gene polymorphisms and schizophrenia in the Japanese population, Biol Psychiatry 56 (2004), pp. 10–17. Article | PDF (205 K) | View Record in Scopus | Cited By in Scopus (11)

Kamboh, 2004 M.I. Kamboh, Molecular genetics of late-onset Alzheimer's disease, Ann Hum Genet 68 (2004), pp. 381–404. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (61)

Kikuchi et al., 2003 K. Kikuchi, S. Arawaka, S. Koyama, H. Kimura, C.H. Ren, M. Wada, T. Kawanami, K. Kurita, M. Daimon, S. Kawakatsu, T. Kadoya, K. Goto and T. Kato, An N-terminal fragment of ProSAAS (a granin-like neuroendocrine peptide precursor) is associated with tau inclusions in Pick's disease, Biochem Biophys Res Commun 308 (2003), pp. 646–654. Article | PDF (447 K) | View Record in Scopus | Cited By in Scopus (5)

Kirchmair et al., 1993 R. Kirchmair, R. Hogue-Angeletti, J. Gutierrez, R. Fischer-Colbrie and H. Winkler, Secretoneurin—a neuropeptide generated in brain, adrenal medulla and other endocrine tissues by proteolytic processing of secretogranin: II (chromogranin C), Neuroscience 53 (1993), pp. 359–365. Abstract | PDF (1679 K) | View Record in Scopus | Cited By in Scopus (141)

Kitao et al., 2000 Y. Kitao, T. Inada, T. Arinami, C. Hirotsu, S. Aoki, Y. Iijima, T. Yamauchi and G. Yagi, A contribution to genome-wide association studies: search for susceptibility loci for schizophrenia using DNA microsatellite markers on chromosomes 19, 20, 21 and 22, Psychiatr Genet 10 (2000), pp. 139–143. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (7)

Koshimizu et al., 2010 H. Koshimizu, T. Kim, N.X. Cawley and Y.P. Loh, Chromogranin A: a new proposal for trafficking, processing and induction of granule biogenesis, Regul Pept 160 (2010), pp. 153–159. Article | PDF (2681 K) | View Record in Scopus | Cited By in Scopus (1)

Landén et al., 1999a M. Landén, P. Davidsson, C.G. Gottfries, B. Grenfeldt, M. Stridsberg and K. Blennow, Reduction of the small synaptic vesicle protein synaptophysin but not the large dense core chromogranins in the left thalamus of subjects with schizophrenia, Biol Psychiatry 46 (1999), pp. 1698–1702. Article | PDF (37 K) | View Record in Scopus | Cited By in Scopus (25)

Landén et al., 1999b M. Landén, B. Grenfeldt, P. Davidsson, M. Stridsberg, B. Regland, C.G. Gottfries and K. Blennow, Reduction of chromogranin A and B but not C in the cerebrospinal fluid in subjects with schizophrenia, Eur Neuropsychopharmacol 9 (1999), pp. 311–315. Article | PDF (61 K) | View Record in Scopus | Cited By in Scopus (16)

Lechner et al., 2004 T. Lechner, C. Adlassnig, C. Humpel, W.A. Kaufmann, H. Maier, K. Reinstadler-Kramer, J. Hinterhölzl, S.K. Mahata, K.A. Jellinger and J. Marksteiner, Chromogranin peptides in Alzheimer's disease, Exp Gerontol 39 (2004), pp. 101–113. Article | PDF (468 K) | View Record in Scopus | Cited By in Scopus (16)

Lee et al., 2001 V.M. Lee, M. Goedert and J.Q. Trojanowski, Neurodegenerative tauopathies, Annu Rev Neurosci 24 (2001), pp. 1121–1159. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (761)

Levi et al., 1985 A. Levi, J.D. Eldridge and B.M. Paterson, Molecular cloning of a gene sequence regulated by nerve growth factor, Science 229 (1985), pp. 393–395. View Record in Scopus | Cited By in Scopus (85)

Levi et al., 2004 A. Levi, G.L. Ferri, E. Watson, R. Possenti and S.R. Salton, Processing, distribution, and function of VGF, a neuronal and endocrine peptide precursor, Cell Mol Neurobiol 24 (2004), pp. 517–533. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (32)

Mahata et al., 1997 S.K. Mahata, D.T. O'Connor, M. Mahata, S.H. Yoo, L. Taupenot, H. Wu, B.M. Gill and R.J. Parmer, Novel autocrine feedback control of catecholamine release: A discrete chromogranin a fragment is a noncompetitive nicotinic cholinergic antagonist, J Clin Invest 100 (1997), pp. 1623–1633. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (154)

Maruyama et al., 2010 H. Maruyama, H. Morino, H. Ito, Y. Izumi, H. Kato, Y. Watanabe, Y. Kinoshita, M. Kamada, H. Nodera, H. Suzuki, O. Komure, S. Matsuura, K. Kobatake, N. Morimoto, K. Abe, N. Suzuki, M. Aoki, A. Kawata, T. Hirai, T. Kato, K. Ogasawara, A. Hirano, T. Takumi, H. Kusaka, K. Hagiwara, R. Kaji and H. Kawakami, Mutations of optineurin in amyotrophic lateral sclerosis, Nature 465 (2010), pp. 223–226. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (0)

Mattsson et al., 2007 N. Mattsson, U. Rüetschi, V.N. Podust, M. Stridsberg, S. Li, O. Andersen, S. Haghighi, K. Blennow and H. Zetterberg, Cerebrospinal fluid concentrations of peptides derived from chromogranin B and secretogranin II are decreased in multiple sclerosis, J Neurochem 103 (2007), pp. 1932–1939. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (2)

Miller et al., 1996 C. Miller, R. Kirchmair, J. Troger, A. Saria, W.W. Fleischhacker, R. Fischer-Colbrie, A. Benzer and H. Winkler, CSF of neuroleptic-naive first-episode schizophrenic patients: levels of biogenic amines, substance P, and peptides derived from chromogranin A (GE-25) and secretogranin II (secretoneurin), Biol Psychiatry 39 (1996), pp. 911–918. Abstract | PDF (728 K) | View Record in Scopus | Cited By in Scopus (25)

Moss et al., 2008 A. Moss, R. Ingram, S. Koch, A. Theodorou, L. Low, M. Baccei, G.J. Hathway, M. Costigan, S.R. Salton and M. Fitzgerald, Origins, actions and dynamic expression patterns of the neuropeptide VGF in rat peripheral and central sensory neurones following peripheral nerve injury, Mol Pain 4 (2008), p. 62. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (1)

Munoz, 1991 D.G. Munoz, Chromogranin A-like immunoreactive neurites are major constituents of senile plaques, Lab Invest 64 (1991), pp. 826–832. View Record in Scopus | Cited By in Scopus (47)

Nowakowski et al., 2002 C. Nowakowski, W.A. Kaufmann, C. Adlassnig, H. Maier, K. Salimi, K.A. Jellinger and J. Marksteiner, Reduction of chromogranin B-like immunoreactivity in distinct subregions of the hippocampus from individuals with schizophrenia, Schizophr Res 58 (2002), pp. 43–53. Article | PDF (847 K) | View Record in Scopus | Cited By in Scopus (20)

Obayashi et al., 2008 K. Obayashi, K. Sato, R. Shimazaki, T. Ishikawa, K. Goto, H. Ueyama, T. Mori, Y. Ando and T. Kumamoto, Salivary chromogranin A: useful and quantitative biochemical marker of affective state in patients with amyotrophic lateral sclerosis, Intern Med 47 (2008), pp. 1875–1879. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (2)

O'Connor et al., 1993 D.T. O'Connor, M.T. Kailasam and L.J. Thal, Cerebrospinal fluid chromogranin A is unchanged in Alzheimer dementia, Neurobiol Aging 14 (1993), pp. 267–269. Abstract | PDF (286 K) | View Record in Scopus | Cited By in Scopus (7)

Pasinetti et al., 2006 G.M. Pasinetti, L.H. Ungar, D.J. Lange, S. Yemul, H. Deng, X. Yuan, R.H. Brown, M.E. Cudkowicz, K. Newhall, E. Peskind, S. Marcus and L. Ho, Identification of potential CSF biomarkers in ALS, Neurology 66 (2006), pp. 1218–1222. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (56)

Riedl et al., 2009 M.S. Riedl, P.D. Braun, K.F. Kitto, S.A. Roiko, L.B. Anderson, C.N. Honda, C.A. Fairbanks and L. Vulchanova, Proteomic analysis uncovers novel actions of the neurosecretory protein VGF in nociceptive processing, J Neurosci 29 (2009), pp. 13377–13388. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (0)

Rizzi et al., 2008 R. Rizzi, A. Bartolomucci, A. Moles, F. D'Amato, P. Sacerdote, A. Levi, G. La Corte, M.T. Ciotti, R. Possenti and F. Pavone, The VGF-derived peptide TLQP-21: a new modulatory peptide for inflammatory pain, Neurosci Lett 441 (2008), pp. 129–133. Article | PDF (648 K) | View Record in Scopus | Cited By in Scopus (1)

Rosa and Zanini , 198l Rosa P, Zanini A (198l) Characterization of adenohypophysial polypeptides by two-dimensional gel electrophoresis: II. Sulfated and glycosylated polypeptides. Mol Cell Endocrinol 24:181–193.

Rosen et al., 1993 D.R. Rosen, T. Siddique, D. Patterson, D.A. Figlewicz, P. Sapp, A. Hentati, D. Donaldson, J. Goto, J.P. O'Regan and H.X. Deng et al., Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis, Nature 362 (1993), pp. 59–62. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (2326)

Rüetschi et al., 2005 U. Rüetschi, H. Zetterberg, V.N. Podust, J. Gottfries, S. Li, Simonsen A. Hviid, J. McGuire, M. Karlsson, L. Rymo, H. Davies, L. Minthon and K. Blennow, Identification of CSF biomarkers for frontotemporal dementia using SELDI-TOF, Exp Neurol 196 (2005), pp. 273–281. Article | PDF (560 K) | View Record in Scopus | Cited By in Scopus (34)

Sahu et al., 2010 B.S. Sahu, P.J. Sonawane and N.R. Mahapatra, Chromogranin A: a novel susceptibility gene for essential hypertension, Cell Mol Life Sci 67 (2010), pp. 861–874. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (0)

Salton et al., 2000 S.R. Salton, G.L. Ferri, S. Hahm, S.E. Snyder, A.J. Wilson, R. Possenti and A. Levi, VGF: a novel role for this neuronal and neuroendocrine polypeptide in the regulation of energy balance, Front Neuroendocrinol 21 (2000), pp. 199–219. Abstract | PDF (372 K) | View Record in Scopus | Cited By in Scopus (57)

Salton et al., 1991 S.R. Salton, D.J. Fischberg and K.W. Dong, Structure of the gene encoding VGF, a nervous system-specific mRNA that is rapidly and selectively induced by nerve growth factor in PC12 cells, Mol Cell Biol 11 (1991), pp. 2335–2349. View Record in Scopus | Cited By in Scopus (52)

Schiffer et al., 1995 D. Schiffer, S. Cordera, M.T. Giordana, A. Attanasio and T. Pezzulo, Synaptic vesicle proteins, synaptophysin and chromogranin A in amyotrophic lateral sclerosis, J Neurol Sci 129 (1995), pp. 68–74. Abstract | PDF (2258 K) | View Record in Scopus | Cited By in Scopus (10)

Schrott-Fischer et al., 2009 A. Schrott-Fischer, M. Bitsche, C. Humpel, C. Walcher, H. Maier, K. Jellinger, W. Rabl, R. Glueckert and J. Marksteiner, Chromogranin peptides in amyotrophic lateral sclerosis, Regul Pept 152 (2009), pp. 13–21. Article | PDF (3123 K) | View Record in Scopus | Cited By in Scopus (4)

Severini et al., 2009 C. Severini, G. La Corte, G. Improta, M. Broccardo, S. Agostini, C. Petrella, V. Sibilia, F. Pagani, F. Guidobono, I. Bulgarelli, G.L. Ferri, C. Brancia, A.M. Rinaldi, A. Levi and R. Possenti, In vitro and in vivo pharmacological role of TLQP-21, a VGF-derived peptide, in the regulation of rat gastric motor functions, Br J Pharmacol 157 (2009), pp. 984–993. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (1)

Simonsen et al., 2007 A.H. Simonsen, J. McGuire, V.N. Podust, N.O. Hagnelius, T.K. Nilsson, E. Kapaki, D. Vassilopoulos and G. Waldemar, A novel panel of cerebrospinal fluid biomarkers for the differential diagnosis of Alzheimer's disease versus normal aging and frontotemporal dementia, Dement Geriatr Cogn Disord 24 (2007), pp. 434–440. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (11)

Snyder and Salton, 1998 S.E. Snyder and S.R. Salton, Expression of VGF mRNA in the adult rat central nervous system, J Comp Neurol 394 (1998), pp. 91–105. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (25)

Sonnen et al., 2008 J.A. Sonnen, K.S. Montine, J.F. Quinn, J.A. Kaye, J.C. Breitner and T.J. Montine, Biomarkers for cognitive impairment and dementia in elderly people, Lancet Neurol 7 (2008), pp. 704–714. Article | PDF (135 K) | View Record in Scopus | Cited By in Scopus (9)

Sreedharan et al., 2008 J. Sreedharan, I.P. Blair, V.B. Tripathi, X. Hu, C. Vance, B. Rogelj, S. Ackerley, J.C. Durnall, K.L. Williams, E. Buratti, F. Baralle, J. de Belleroche, J.D. Mitchell, P.N. Leigh, A. Al-Chalabi, C.C. Miller, G. Nicholson and C.E. Shaw, TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis, Science 319 (2008), pp. 1668–1672. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (232)

Stoop et al., 2008 M.P. Stoop, L.J. Dekker, M.K. Titulaer, P.C. Burgers, P.A. Sillevis Smitt, T.M. Luider and R.Q. Hintzen, Multiple sclerosis-related proteins identified in cerebrospinal fluid by advanced mass spectrometry, Proteomics 8 (2008), pp. 1576–1585. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (9)

Stoop et al., 2009 M.P. Stoop, L.J. Dekker, M.K. Titulaer, R.J. Lamers, P.C. Burgers, P.A. Sillevis Smitt, A.J. van Gool, T.M. Luider and R.Q. Hintzen, Quantitative matrix-assisted laser desorption ionization-fourier transform ion cyclotron resonance (MALDI-FT-ICR) peptide profiling and identification of multiple-sclerosis-related proteins, J Proteome Res 8 (2009), pp. 1404–1414. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (3)

Takahashi et al., 2006 N. Takahashi, R. Ishihara, S. Saito, N. Maemo, N. Aoyama, X. Ji, H. Miura, M. Ikeda, N. Iwata, T. Suzuki, T. Kitajima, Y. Yamanouchi, Y. Kinoshita, N. Ozaki and T. Inada, Association between chromogranin A gene polymorphism and schizophrenia in the Japanese population, Schizophr Res 83 (2006), pp. 179–183. Article | PDF (158 K) | View Record in Scopus | Cited By in Scopus (1)

Taupenot et al., 2003 L. Taupenot, K.L. Harper and D.T. O'Connor, The chromogranin-secretogranin family, N Engl J Med 348 (2003), pp. 1134–1149. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (282)

Thakker-Varia et al., 2007 S. Thakker-Varia, J.J. Krol, J. Nettleton, P.M. Bilimoria, D.A. Bangasser, T.J. Shors, I.B. Black and J. Alder, The neuropeptide VGF produces antidepressant-like behavioural effects and enhances proliferation in the hippocampus, J Neurosci 27 (2007), pp. 12156–12167. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (26)

Toshinai and Nakazato, 2009 K. Toshinai and M. Nakazato, Neuroendocrine regulatory peptide-1 and -2: novel bioactive peptides processed from VGF, Cell Mol Life Sci 66 (2009), pp. 1939–1945. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (0)

Toshinai et al., in press Toshinai K, Yamaguchi H, Kageyama H, Matsuo T, Koshinaka K, Sasaki K, Shioda S, Minamino N, Nakazato M (in press) Neuroendocrine regulatory peptide-2 regulates feeding behavior via the orexin system in the hypothalamus. Am J Physiol Endocrinol Metab. doi: 10.1152/ajpendo.00768.2009.

Trani et al., 1995 E. Trani, T. Ciotti, A.M. Rinaldi, N. Canu, G.L. Ferri, A. Levi and R. Possenti, Tissue-specific processing of the neuroendocrine protein VGF, J Neurochem 65 (1995), pp. 2441–2449. View Record in Scopus | Cited By in Scopus (37)

Urushitani et al., 2006 M. Urushitani, A. Sik, T. Sakurai, N. Nukina, R. Takahashi and J.P. Julien, Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis, Nat Neurosci 9 (2006), pp. 108–118. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (107)

van Kammen et al., 1991 D.P. van Kammen, J. Peters, J. Yao, T. Neylan, M. Beuger, E. Pontius and D.T. O'Connor, CSF chromogranin A-like immunoreactivity in schizophrenia: Assessment of clinical and biochemical relationships, Schizophr Res 6 (1991), pp. 31–39. Abstract | PDF (810 K) | View Record in Scopus | Cited By in Scopus (6)

Wada et al., 2004 M. Wada, C.H. Ren, S. Koyama, S. Arawaka, S. Kawakatsu, H. Kimura, H. Nagasawa, T. Kawanami, K. Kurita, M. Daimon, A. Hirano and T. Kato, A human granin-like neuroendocrine peptide precursor (proSAAS) immunoreactivity in tau inclusions of Alzheimer's disease and parkinsonism-dementia complex on Guam, Neurosci Lett 356 (2004), pp. 49–52. Article | PDF (162 K) | View Record in Scopus | Cited By in Scopus (3)

Weiler et al., 1990 R. Weiler, H. Lassmann, P. Fischer, K. Jellinger and H. Winkler, A high ratio of chromogranin A to synaptin/synaptophysin is a common feature of brains in Alzheimer and Pick disease, FEBS Lett 263 (1990), pp. 337–339. Abstract | PDF (387 K) | View Record in Scopus | Cited By in Scopus (31)

Winkler and Fischer-Colbrie, 1992 H. Winkler and R. Fischer-Colbrie, The chromogranins A and B: the first 25 years and future perspectives, Neuroscience 49 (1992), pp. 497–528. Abstract | PDF (4620 K) | View Record in Scopus | Cited By in Scopus (391)

Yajima et al., 2004 A. Yajima, M. Ikeda, K. Miyazaki, T. Maeshima, N. Narita and M. Narita, Manserin, a novel peptide from secretogranin II in the neuroendocrine system, Neuroreport 15 (2004), pp. 1755–1759. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (7)

Yamaguchi et al., 2007 H. Yamaguchi, K. Sasaki, Y. Satomi, T. Shimbara, H. Kageyama, M.S. Mondal, K. Toshinai, Y. Date, L.J. González, S. Shioda, T. Takao, M. Nakazato and N. Minamino, Peptidomic identification and biological validation of neuroendocrine regulatory peptide-1 and -2, J Biol Chem 282 (2007), pp. 26354–26360. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (10)

Yasuhara et al., 1994 O. Yasuhara, T. Kawamata, Y. Aimi, E.G. McGeer and P.L. McGeer, Expression of chromogranin A in lesions in the central nervous system from patients with neurological diseases, Neurosci Lett 170 (1994), pp. 13–16. Abstract | PDF (870 K) | View Record in Scopus | Cited By in Scopus (35)

Zhao et al., 2008 Z. Zhao, D.J. Lange, L. Ho, S. Bonini, B. Shao, S.R. Salton, S. Thomas and G.M. Pasinetti, Vgf is a novel biomarker associated with muscle weakness in amyotrophic lateral sclerosis (ALS), with a potential role in disease pathogenesis, Int J Med Sci 5 (2008), pp. 92–99. View Record in Scopus | Cited By in Scopus (4)

Correspondence to: A. Bartolomucci, Department of Evolutionary and Functional Biology, University of Parma, 43124 Parma, Italy. Tel: +39-0521906175; fax: +39-0521905657 or S. R. J. Salton, Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA. Tel:
¹ Present address: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA.

¹ Throughout the text we refer to the proteins by their published names. We note here as well the secretogranin nomenclature (SgX) introduced by Helle (2004) to convey the notion that they are a structurally and functionally related class of proteins.
² Internal fragments of a protein are conventionally identified with the amino acid position number (first and last) in the propeptide sequence, which can be found for most proteins in the NIH database accessible via web at http://www.ncbi.nlm.nih.gov/protein.

Note to users: The section "Articles in Press" contains peer reviewed accepted articles to be published in this journal. When the final article is assigned to an issue of the journal, the "Article in Press" version will be removed from this section and will appear in the associated published journal issue. The date it was first made available online will be carried over. Please be aware that although "Articles in Press" do not have all bibliographic details available yet, they can already be cited using the year of online publication and the DOI as follows: Author(s), Article Title, Journal (Year), DOI. Please consult the journal's reference style for the exact appearance of these elements, abbreviation of journal names and the use of punctuation.

There are three types of "Articles in Press":

Accepted manuscripts: these are articles that have been peer reviewed and accepted for publication by the Editorial Board. The articles have not yet been copy edited and/or formatted in the journal house style. Uncorrected proofs: these are copy edited and formatted articles that are not yet finalized and that will be corrected by the authors. Therefore the text could change before final publication. Corrected proofs: these are articles containing the authors' corrections and may, or may not yet have specific issue and page numbers assigned.

---

Neuroscience Article in Press, Uncorrected Proof - Note to users