Discovery and verification of amyotrophic lateral sclerosis biomarkers by proteomics

Ryberg, Henrik; An, Jiyan; Darko, Samuel; Lustgarten, Jonathan L.; Jaffa, Matt; Gopalakrishnan, Vanathi; Lacomis, David; Cudkowicz, Merit; Bowser, Robert

doi:10.1002/mus.21683

Cited by 110 publications

(91 citation statements)

References 40 publications

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“…Immobilization, disuse or denervation triggers muscular atrophy, which clearly shows that neuromuscular innervation patterns are directly linked to gene expression, protein abundance and isoform patterns in skeletal muscles [29]. In analogy to the recent proteomic profiling of cerebrospinal fluids from patients suffering from ALS and the spinal cord from the wobbler mouse [19][20][21][22][23], this study describes the findings of the MS-based proteomic survey of skeletal muscle from the WR mouse. From the detailed analysis of the isoform patterns of the sarcomeric MyHCs it became clear that the response of gene expression in skeletal muscle to denervation is characteristically different from that to hyper-excitability and muscular dystrophy [28].…”

Section: Resultsmentioning

confidence: 97%

“…The current international effort to discover reliable biomarkers of ALS [16] includes the verification of both suitable metabolites [17] and protein factors [18]. Recent proteomic profiling studies of ALS patient samples and the WR animal model have focused on the analysis of cerebrospinal fluid [19][20][21] and cervical and lumbar spinal cord [22,23], respectively. The studies on the WR mouse showed that the majority of differentially expressed proteins were related to the glutamate-glutamine cycle, energy transduction, redox functions and astrogliosis [22], thus confirming previous studies [24].…”

Section: Introductionmentioning

confidence: 99%

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Proteomic analysis of muscle affected by motor neuron degeneration: The wobbler mouse model of amyotrophic lateral sclerosis

Staunton

Jockusch

Ohlendieck

2011

Biochemical and Biophysical Research Communications

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a b s t r a c tAmyotrophic lateral sclerosis is the most common form of motor neuron disease in adult patients and characterized by progressive paralysis. The wobbler mouse (phenotype WR, genotype wr/wr) is an established animal model of human motor neuron disease and is characterized by a large variety of cellular abnormalities including muscular atrophy. In analogy to recent proteomic studies of cerebrospinal fluid and spinal cord, we have used here fluorescence difference in-gel electrophoresis to analyze global changes in the skeletal muscle proteome from WR versus normal mice. Relative concentrations of 21 proteins were found to be increased and 3 proteins were decreased. Mass spectrometric analysis identified these proteins to be associated with key metabolic pathways, the contractile apparatus, intermediate filaments and the cellular stress response. Drastically increased levels of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase were confirmed by immunoblotting and this finding agrees with the idea of an oxidative-to-glycolytic shift in disease-related muscular atrophy. The establishment of novel disease-specific biomarkers of motor neuron disease might be helpful in the design of improved diagnostic tools and the identification of novel therapeutic targets.

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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Proteomic analysis of muscle affected by motor neuron degeneration: The wobbler mouse model of amyotrophic lateral sclerosis

Staunton

Jockusch

Ohlendieck

2011

Biochemical and Biophysical Research Communications

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“…Previous efforts in our group, as well as others, identified cystatin C as a potential biomarker in the CSF of patients with ALS [49,[97][98][99][100]. Cystatin C is a cysteine protease inhibitor that is involved in extracellular matrix (ECM) regulation, as well as a variety of CNS diseases [101,102].…”

Section: Cystatin Cmentioning

confidence: 98%

“…Using surfaceenhanced laser desorption/ionization, reduced levels of cystatin C were observed in CSF from patients with ALS as compared with control subjects (healthy and diseased) [97]. Levels of cystatin C positively correlated with survival time for patients with limb onset but did not correlate with the disease duration [98]. A longitudinal study was also performed on CSF and plasma over a 1 to 2-year time period [105].…”

Section: Cystatin Cmentioning

confidence: 99%

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Bowser

2017

Neurotherapeutics

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Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease with no effective treatment. Drug development has been hampered by the lack of biomarkers that aid in early diagnosis, demonstrate target engagement, monitor disease progression, and can serve as surrogate endpoints to assess the efficacy of treatments. Fluid-based biomarkers may potentially address these issues. An ideal biomarker should exhibit high specificity and sensitivity for distinguishing ALS from control (appropriate disease mimics and other neurologic diseases) populations and monitor disease progression within individual patients. Significant progress has been made using cerebrospinal fluid, serum, and plasma in the search for ALS biomarkers, with urine and saliva biomarkers still in earlier stages of development. A few of these biomarker candidates have demonstrated use in patient stratification, predicting disease course (fast vs slow progression) and severity, or have been used in preclinical and clinical applications. However, while ALS biomarker discovery has seen tremendous advancements in the last decade, validating biomarkers and moving them towards the clinic remains more elusive. In this review, we highlight biomarkers that are moving towards clinical utility and the challenges that remain in order to implement biomarkers at all stages of the ALS drug development process.

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“…These differences can be used to develop biomarkers of disease and provide insights into disease pathogenesis. Feasibility of a proteomics approach as well as disease-relevant changes have been described in both plasma (12)(13)(14) and cerebrospinal fluid (15)(16)(17), highlighting the utility of proteomics in biomarker development. We, and others, have also demonstrated the potential for this approach in identifying neurodegenerative-specific changes in postmortem brain tissues.…”

mentioning

confidence: 99%

U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer’s disease

Bai

Hales

Chen³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

275

366

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Deposition of insoluble protein aggregates is a hallmark of neurodegenerative diseases. The universal presence of β-amyloid and tau in Alzheimer's disease (AD) has facilitated advancement of the amyloid cascade and tau hypotheses that have dominated AD pathogenesis research and therapeutic development. However, the underlying etiology of the disease remains to be fully elucidated. Here we report a comprehensive study of the human brain-insoluble proteome in AD by mass spectrometry. We identify 4,216 proteins, among which 36 proteins accumulate in the disease, including U1-70K and other U1 small nuclear ribonucleoprotein (U1 snRNP) spliceosome components. Similar accumulations in mild cognitive impairment cases indicate that spliceosome changes occur in early stages of AD. Multiple U1 snRNP subunits form cytoplasmic tangle-like structures in AD but not in other examined neurodegenerative disorders, including Parkinson disease and frontotemporal lobar degeneration. Comparison of RNA from AD and control brains reveals dysregulated RNA processing with accumulation of unspliced RNA species in AD, including myc boxdependent-interacting protein 1, clusterin, and presenilin-1. U1-70K knockdown or antisense oligonucleotide inhibition of U1 snRNP increases the protein level of amyloid precursor protein.Thus, our results demonstrate unique U1 snRNP pathology and implicate abnormal RNA splicing in AD pathogenesis.proteomics | liquid chromatography-tandem mass spectrometry | U1A | RNA-seq | premature cleavage and polyadenylation

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Discovery and verification of amyotrophic lateral sclerosis biomarkers by proteomics

Cited by 110 publications

References 40 publications

Proteomic analysis of muscle affected by motor neuron degeneration: The wobbler mouse model of amyotrophic lateral sclerosis

Proteomic analysis of muscle affected by motor neuron degeneration: The wobbler mouse model of amyotrophic lateral sclerosis

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer’s disease

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