Ranganathan S, Williams E, Ganchev P, et al. Proteomic profiling of cerebrospinal fluid identifies biomarkers for amyotrophic lateral sclerosis

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Journal of Neurochemistry (Impact Factor: 4.28). 12/2005; 95(5):1461-71. DOI: 10.1111/j.1471-4159.2005.03478.x
Source: PubMed


Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons. We tested the hypothesis that proteomic analysis will identify protein biomarkers that provide insight into disease pathogenesis and are diagnostically useful. To identify ALS specific biomarkers, we compared the proteomic profile of cerebrospinal fluid (CSF) from ALS and control subjects using surface-enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF-MS). We identified 30 mass ion peaks with statistically significant (p < 0.01) differences between control and ALS subjects. Initial analysis with a rule-learning algorithm yielded biomarker panels with diagnostic predictive value as subsequently assessed using an independent set of coded test subjects. Three biomarkers were identified that are either decreased (transthyretin, cystatin C) or increased (carboxy-terminal fragment of neuroendocrine protein 7B2) in ALS CSF. We validated the SELDI-TOF-MS results for transthyretin and cystatin C by immunoblot and immunohistochemistry using commercially available antibodies. These findings identify a panel of CSF protein biomarkers for ALS.

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    • "Similarly, a reduction of cystatin C levels in CSF samples could indicate increased proteolysis via cysteine proteases. However, increased levels of 7B2CT could represent a reactive response to altered enzymatic activities that generate or degrade 7B2CT, or it could result from Golgi fragmentation within motor neurons during ALS [53]. "
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    ABSTRACT: Since amyotrophic lateral sclerosis (ALS) was discovered and described in 1869 as a neurodegenerative disease in which motor neuron death is induced, a wide range of biomarkers have been selected to identify therapeutic targets. ALS shares altered molecular pathways with other neurodegenerative diseases, such as Alzheimer's, Huntington's, and Parkinson's diseases. However, the molecular targets that directly influence its aggressive nature remain unknown. What is the first link in the neurodegenerative chain of ALS that makes this disease so peculiar? In this review, we will discuss the progression of the disease from the viewpoint of the potential biomarkers described to date in human and animal model samples. Finally, we will consider potential therapeutic strategies for ALS treatment and future, innovative perspectives.
    Full-text · Article · Aug 2014 · BioMed Research International
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    • "Référence Validation externe Fluide biologique Nombre de composés analysés Modèle multivarié Biomarqueurs (SLA/contrôles) Voies physiopathologiques Pasinetti et al., 2006 [11] Oui LCR 30 Non Cystatine C # Neuroprotection, métabolisme énergétique, plasticité synaptique Protéines 4.8-kDa # VGF# Ranganathan et al., 2005 [12] "
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    ABSTRACT: Numerous biomarkers studies in ALS used targeted and non-targeted approaches, to help for the diagnosis, the prognosis or to identify new pathophysiological ways. The emerging approaches such as "omics" studies are very promising, but the practical and technical limits do not enable their optimization. Even if some biomarkers such as cystatin C or glutamate are highlighted in ALS, to date, no biomarker is currently used in routine practice. Diffusion-based neuroimaging has emerged as a tool to identify the involvement of the central neuron, but a recent meta-analysis shows a poor sensitivity and specificity. Spinal cord imaging has the advantage of simultaneoulsy investigating both the corticospinal tract and the peripheral motor neurons in the anterior horns of the spinal cord. Its interest to provide biomarkers in ALS is illustrated by recent studies that used a multiparametric approach. The limits of biomarkers studies are principally based on small cohorts, involving a control population who does not allow to assess specificity. The discrepancies between the biomarkers identified in the different studies are based on a strong heterogeneity of the disease and a lack of standardization of the research methodology, including the step of the validation of these molecules in independent cohorts. The perspectives in biomarker research in ALS imply the combination of analytical methods, human abilities and harmonization of the strategies.
    Full-text · Article · Apr 2014 · La Presse Médicale
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    • "Early studies used proteomics to identify oxidatively modified proteins in AD brains, in which creatine kinase BB, glutamine synthase, and ubiquitin carboxy-terminal hydrolase L-1 were revealed as specific targets of protein oxidation in AD (Castegna et al., 2002). More recent studies have used proteomics to identify potential biomarkers involved in several neurodegenerative diseases, including ALS (Ranganathan et al., 2005; Ryberg et al., 2010; Zhou et al., 2010), PD (Chen et al., 2011; Lehnert et al., 2012), and AD (Zabel et al., 2012). Indeed, proteomic Additional Supporting Information may be found in the online version of this article. "
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    ABSTRACT: Understanding the complex biology of the brain requires analyzing its structural and functional complexity at the protein level. The large-scale analysis of the brain proteome, coupled with characterization of central brain proteins, provides insight into fundamental brain processes and processes linked to neurodegenerative diseases. Here we provide a map of the zebrafish brain proteome by using two-dimensional gel electrophoresis (2DE), followed by the identification of 95 brain proteins using mass spectrometry (LC-ESI MS/MS). Our data show extensive phosphorylation of brain proteins but less prominent glycosylation. Furthermore, ∼51% of the identified proteins are predicted to have one or more ubiquitination sites whereas ∼90% are predicted to have one or more SUMOylation sites. Our findings provide a valuable proteome map of the zebrafish brain and associated posttranslational modifications demonstrating that zebrafish proteomic approaches can aid in our understanding of proteins central to important neuronal processes and those associated with neurodegenerative disorders. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Jan 2014 · Journal of Neuroscience Research
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