Proteomics‐driven progress in neurodegeneration research

Fountoulakis, Michael; Κοσσίδα, Σοφία

doi:10.1002/elps.200500738

Cited by 51 publications

(48 citation statements)

References 181 publications

(302 reference statements)

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“…Based on the enormous impact proteomics had on biomedical studies over the last few years [148][149][150], it can be expected that the proteomic profiling of animal disease models will have a considerable influence on the improved design of diagnostic procedures, the evaluation of experimental treatment strategies such as stem cell and gene therapy, and the detailed biochemical phenotyping of new disease model systems. Since end-stage pathologies may involve similar degenerative pathways, it is important to distinguish between common indicators of general cellular destruction and subsets of more precise markers of a particular disease.…”

Section: Discussionmentioning

confidence: 99%

Proteomic profiling of animal models mimicking skeletal muscle disorders

Doran

Gannon

O’Connell

et al. 2007

Proteomics Clinical Apps

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Over the last few decades of biomedical research, animal models of neuromuscular diseases have been widely used for determining pathological mechanisms and for testing new therapeutic strategies. With the emergence of high-throughput proteomics technology, the identification of novel protein factors involved in disease processes has been decisively improved. This review outlines the usefulness of the proteomic profiling of animal disease models for the discovery of new reliable biomarkers, for the optimization of diagnostic procedures and the development of new treatment options for skeletal muscle disorders. Since inbred animal strains show genetically much less interindividual differences as compared to human patients, considerably lower experimental repeats are capable of producing meaningful proteomic data. Thus, animal model proteomics can be conveniently employed for both studying basic mechanisms of molecular pathogenesis and the effects of drugs, genetic modifications or cell-based therapies on disease progression. Based on the results from comparative animal proteomics, a more informed decision on the design of clinical proteomics studies could be reached. Since no one animal model represents a perfect pathobiochemical replica of all of the symptoms seen in complex human disorders, the proteomic screening of novel animal models can also be employed for swift and enhanced protein biochemical phenotyping.

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Section: Discussionmentioning

confidence: 99%

Proteomic profiling of animal models mimicking skeletal muscle disorders

Doran

Gannon

O’Connell

et al. 2007

Proteomics Clinical Apps

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“…Changes in numerous proteins have been reported in postmortem AD brain (for review, see Fountoulakis and Kossida, 2006), and it has been challenging to determine whether a particular protein alteration plays an active role in the disease process, or whether it is a passive bystander caused by end-stage neuronal degeneration and death. One way to address this question is to use an AD animal model that recapitulates critical aspects of disease over time.…”

Section: Bace1 Levels Are Elevated In App Transgenic Mouse and Human mentioning

confidence: 99%

“…However, numerous proteins become elevated in AD (for review, see Fountoulakis and Kossida, 2006) and the AD brain undergoes massive cell death (for review, see Morrison and Hof, 1997), so it is difficult to determine from postmortem brain whether any given change is an epiphenomenon in late-stage AD, or whether it is an early event directly involved in pathogenesis. To address this problem, we investigated whether the BACE1 elevation could be recapitulated in two APP transgenic mouse lines, 5XFAD and Tg2576 (Hsiao et al, 1996), which develop amyloid plaques at young and old ages, and do and do not exhibit neuron loss, respectively.…”

Section: Introductionmentioning

confidence: 99%

β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Levels Become Elevated in Neurons around Amyloid Plaques: Implications for Alzheimer's Disease Pathogenesis

Zhao¹,

Fu²,

Yasvoina³

et al. 2007

J. Neurosci.

328

359

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␤-Site amyloid precursor protein cleaving enzyme 1 (BACE1) (␤-secretase) initiates generation of ␤-amyloid (A␤), which plays an early role in Alzheimer's disease (AD). BACE1 levels are increased in postmortem AD brain, suggesting BACE1 elevation promotes A␤ production and AD. Alternatively, the BACE1 increase may be an epiphenomenon of late-stage AD. To distinguish between these possibilities, we analyzed BACE1 elevation using a highly specific BACE1 antibody, BACE-Cat1, made in BACE1Ϫ/Ϫ mice, which mount a robust anti-BACE1 immune response. Previous BACE1 immunohistochemical studies lack consistent results because typical BACE1 antibodies produce nonspecific background, but BACE-Cat1 immunolabels BACE1 only. BACE1 elevation was recapitulated in two amyloid precursor protein (APP) transgenic mouse lines. 5XFAD mice form amyloid plaques at young ages and exhibit neuron loss. In contrast, Tg2576 form plaques at a more advanced age and do not show cell death. These two mouse lines allow differentiation between early A␤-induced events and late phenomena related to neuron death. BACE1 levels became elevated in parallel with amyloid burden in each APP transgenic, starting early in 5XFAD and late in Tg2576. The increase in BACE1 protein occurred without any change in BACE1 mRNA level, indicating a posttranscriptional mechanism. In APP transgenic and AD brains, high BACE1 levels were observed in an annulus around A␤42-positive plaque cores and colocalized with neuronal proteins. These results demonstrate that amyloid plaques induce BACE1 in surrounding neurons at early stages of pathology before neuron death occurs. We conclude that BACE1 elevation is most likely triggered by the amyloid pathway and may drive a positive-feedback loop in AD.

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“…Proteomics has been widely used in neuroscience and particularly for comparison between healthy individuals and patients suffering from neurodegenerative or other diseases influencing the central nervous system (20), (21) as well as for mapping of proteins in hippocampus to study functions in the central nervous system (22), (23), (24). …”

Section: Proteomicsmentioning

confidence: 99%

Prefractionation of Cerebrospinal Fluid to Enhance Glycoprotein Concentration Prior to Structural Determination with FT−ICR Mass Spectrometry

2005

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När vi leva, låtom oss leva. While we live, let us live. "Let us enjoy life." Dum vivimus vivamus.3 Mass spectrometry for comparative proteomics of degenerative and regenerative processes in the brain ABSTRACT Biological processes involve changes at the protein level which can be detected and quantified. Proteomics aims to determine protein changes from a normal state, for instance to measure the degree of recovery in a biological system or the state of disease progression. Mass spectrometry is the most important tool in proteomics for the identification of proteins and determination of post-translational modifications such as glycosylation. Glycoproteins were found to be altered in patients with Alzheimer's disease (AD), which is the most common form of dementia. Changes in glycosylation levels were quantified with a glycoprotein-specific stain after gel separation. Glycan structures were determined with mass spectrometry in this thesis. Protein quantification with mass spectrometric methods is based on stable isotope labeling of proteins and labeled cell cultures can be used as internal standards for tissue proteomics. Quantitative proteomics was applied to assess protein expression levels with mass spectrometry in the murine brain after specific neurosurgery to study regenerative processes.In order to compare glycosylated proteins in cerebrospinal fluid (CSF) from individual AD patients with healthy control individuals, glycoproteomic methods were developed. To enhance the concentration of glycoproteins prior to gel separation, affinity chromatography of CSF was the most suitable prefractionation method for removing the most abundant CSF protein albumin. CSF proteins were separated with narrow pH-range two-dimensional gel electrophoresis followed by multiple staining for quantification of glycoprotein isoforms. Structural analysis of glycopeptides was performed with Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS), which provided very high mass accuracy and facilitated site-specific determination. A decreased glycosylation level for a protein localized in senile plaques, α 1 -antitrypsin, was found in AD patients. No specific glycoform of the studied proteins could be assigned to AD, emphasizing that further studies should include a larger subject group and cover proteins in various pH intervals. Knowledge of the respective glycoprotein structures in relation to clinical disease parameters may assist in the elucidation of the pathogenesis.In order to study proteins involved in the response of astrocytes and regenerative processes after neurotrauma, a quantitative mass spectrometric method was developed. Astrocytes, which are the most abundant cells in the central nervous system, react to neurotrauma by becoming reactive (reactive gliosis). Mice lacking the intermediate filament proteins GFAP and vimentin (GFAP -/-Vim -/-) show attenuated reactive gliosis and enhanced regeneration after neurotrauma. Comparative proteomic analysis showed upregulation of the adapter protein 14-3-3 in wildt...

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Proteomics‐driven progress in neurodegeneration research

Cited by 51 publications

References 181 publications

Proteomic profiling of animal models mimicking skeletal muscle disorders

Proteomic profiling of animal models mimicking skeletal muscle disorders

β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Levels Become Elevated in Neurons around Amyloid Plaques: Implications for Alzheimer's Disease Pathogenesis

Prefractionation of Cerebrospinal Fluid to Enhance Glycoprotein Concentration Prior to Structural Determination with FT−ICR Mass Spectrometry

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