漸凍人纖維母細胞誘導多功能幹細胞之亞細胞蛋白質體定量分析

江鳳玟

doi:10.6845/NCHU.2015.01204

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漸凍人纖維母細胞誘導多功能幹細胞之亞細胞蛋白質體定量分析

Quantitative Analysis of Subcellular Proteome of Amyotrophic Lateral Sclerosis (ALS) Induced Pluripotent Stem Cells (iPSCs)

江鳳玟 , Masters　　Advisor：楊明德　　Co-advisor ：陳玉如

英文 DOI： 10.6845/NCHU.2015.01204

肌萎縮性側索硬化症；誘導多能幹細胞；高解析逆向層析分群技術；陽離子交換層析法；相對和絕對定量等重標籤標記； ALS ； TDP43 ； iPSc ； iTRAQ ； reversed-phase StagTips fractionation ； strong cation exchange chromatography

Abstract │ Reference (97) │ Altmetrics

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Amyotrophic lateral sclerosis (ALS) is the most common form of adult-onset motor neuron disease and the third most common neurodegenerative disease worldwide. The clinical and pathological features are the upper and lower motor neurons degeneration, resulting in progressive muscle atrophy, weakness and paralysis, and finally respiratory failure and death. About 10% of ALS cases are dominantly inherited while the remaining 90% of ALS patents are labeled as sporadic ALS case with largely unknown genetic etiology. In addition to the known genetic defect in SOD1, TDP43 has been discovered as a major component of the pathological and ubiquitinated protein aggregates found in most of the degenerating motor neurons of ALS patients. The identification of the mutations in the gene encoding TDP43 cause some cases of familial and sporadic ALS has extended our understanding toward ALS pathogenesis. However, the pathogenic processes underlying ALS are multifactorial and not fully determined yet. Most seriously, there is no effective treatment for now. In order to explore the molecular mechanisms underlying the TDP43-caused ALS, we used induced pluripotent stem cells (iPSCs) as a model and developed a comprehensive quantitative proteomic strategy at subproteome level to compare the normal- and TDP43 mutation-derived ALS iPSCs. By this comprehensive and differential protein expression map, the ultimate goal is to investigate the perturbed protein factors and signaling pathways. 
To achieve the goal, we have integrated centrifugal separation for enrichment of membrane subproteome, cytoplasmic suproteome and nuclear subproteome, peptide fractionation by reversed-phase StagTips fractionation and strong cation exchange chromatography method, Isobaric Tag for Relative and Absolute Quantitation (iTRAQ) labeling, following by LC-MS/MS analysis. The reversed-phase StagTips fractionation and MS methods have been optimized to improve the number of protein identification and quantification. Using iPS cells derived from two normal male (foreskin fibroblast) and two female patients (skin fibroblast), the subproteomic analysis revealed 6852, 6012 and 1900 identified proteins in the nucleus, cytoplasm and membrane proteome, respectively. Among the total of 8450 identified proteins, 155 and 149 proteins were found to have consistent up-regulation and down-regulation in both patient-derived iPSCs. Several protein products of ALS-related genes such as TDP43, FUS, UBQLN2, ANXA1, AIFM1 and UCHL1 were identified. The systematic investigation of aberrant molecular profiles in TDP43 mutation-derived ALS iPSCs revealed numerous factors and signaling pathways that might lead to initiation of ALS disease, such as oxidative stress, mitochondria dysfunction, neuroinflammation and actin cytoskeleton signaling. Among these pathways, a list of significantly changed protein such as FUS, ANXA1 and PTGR1 have common differential expression associated with TDP43 mutation-derived ALS, which may suggest their central roles in these molecular mechanism. The functional study of these proteins is on-going. We expect that our result will help to delineate the pathomechanism of ALS, to identify modifiers of ALS progression and to pave the way for the development of potential therapeutic strategies in the future.

Reference ( 97 ) 〈TOP〉

1 Chio, A., Calvo, A., Moglia, C., Mazzini, L. & Mora, G. Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study. Journal of neurology, neurosurgery, and psychiatry 82, 740-746, doi:10.1136/jnnp.2010.235952 (2011).
連結：
2 Renton, A. E., Chiò, A. & Traynor, B. J. State of play in amyotrophic lateral sclerosis genetics. Nature neuroscience 17, 17-23 (2014).
連結：
3 Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257-268, doi:10.1016/j.neuron.2011.09.010 (2011).
連結：
4 Wu, C. H. et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488, 499-503, doi:10.1038/nature11280 (2012).
連結：
5 Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science (New York, N.Y.) 319, 1668-1672 (2008).
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