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: 4.24). 12/2005; 95(5):1461-71. DOI: 10.1111/j.1471-4159.2005.03478.x
Source: PubMed

ABSTRACT 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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    ABSTRACT: The common human neurodegenerative disorders such as Amyotrophic lateral sclerosis (ALS), Alzheimer's (AD) and Parkinson's diseases (PD) are a heterogeneous group of neurologic disorders that are characterized by the progressive loss of brain function. In ALS, selective and relentless degeneration occurs in both upper and lower motor neurons, resulting in mortality usually within 5 years of symptom onset. However, surviving rates vary among individual patients that can be from a few months to >10 years. Inadequacy in disease detection, treatment as well as lack of diagnostic and prognostic tools have prompted many to turn to proteomics-based biomarker discovery efforts. Proteomics refer to the study of the proteins expressed by a genome at a particular time in a whole cell or a tissue etc. and the proteome can respond to and reflects the status of an organism including health and disease states. Although an emerging field proteomics application promise to uncover biomarkers critical for differentiating patients with neurodegenerative diseases from healthy people and from patients affected by other diseases. These studies will also contribute mechanistic information to facilitate identification of new drug targets for subsequent therapeutic development. In addition to proper experimental conception, standard operating technique for sample procurement, pre-processing, and storage must be developed. Biological samples generally analyzed in proteomic studies of neurologic diseases include both plasma and cerebro spinal fluid. Recent studies have identified individual protein or protein panels from blood plasma and CSF that represent putative biomarkers for neurodegenerative diseases like AD and ALS, although many of these proteins are not unique to this disease. Continued research investigations are required to validate these initial findings and to further pursue the role of these proteins as diagnostic biomarkers or surrogate markers of disease progression. Protein biomarkers specific to amyotrophic lateral sclerosis (ALS) will additionally function to evaluate drug efficacy in clinical trials and to identify novel targets for drug design. It is hoped that proteomic based technologies will soon integrate the basic biology of neurologic disorders with mechanistic disease information to achieve success in the clinical setting.
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    Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 07/2014; · 2.59 Impact Factor
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    ABSTRACT: While the long-term physiological adaptation of the neuromuscular system to changed functional demands is usually reflected by unilateral skeletal muscle transitions, the progressive degeneration of distinct motor neuron populations is often associated with more complex changes in the abundance and/or isoform expression pattern of contractile proteins and metabolic enzymes. In order to evaluate these intricate effects of primary motor neuronopathy on the skeletal muscle proteome, label-free mass spectrometry was employed to study global alterations in the wobbler mouse model of progressive neurodegeneration. In motor neuron disease, fibre type specification and the metabolic weighting of bioenergetic pathways appear to be strongly influenced by both a differing degree of a subtype-specific vulnerability of neuromuscular synapses and compensatory mechanisms of fibre type shifting. Proteomic profiling confirmed this pathobiochemical complexity of disease-induced changes and showed distinct alterations in 72 protein species, including a variety of fibre type-specific isoforms of contractile proteins, metabolic enzymes, metabolite transporters and ion-regulatory proteins, as well as changes in molecular chaperones and various structural proteins. Increases in slow myosin light chains and the troponin complex and a decrease in fast myosin binding protein probably reflect the initial preferential loss of the fast type of neuromuscular synapses in motor neuron disease.
    Bioscience Reports 06/2014; · 1.88 Impact Factor

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