The Protein-Protein Interaction Network of Hereditary Parkinsonism Genes Is a Hierarchical Scale-Free Network
1
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
Purpose: Hereditary parkinsonism genes consist of causative genes of familial Parkinson’s disease (PD) with a locus symbol prefix(PARK genes) and hereditary atypical parkinsonian disorders that present atypical features and limited responsiveness to levodopa(non-PARK genes). Although studies have shown that hereditary parkinsonism genes are related to idiopathic PD at the phenotyp ic, gene expression, and genomic levels, no study has systematically investigated connectivity among the proteins encoded bythese genes at the protein-protein interaction (PPI) level. Materials and Methods: Topological measurements and physical interaction enrichment were performed to assess PPI networksconstructed using some or all the proteins encoded by hereditary parkinsonism genes (n=96), which were curated using the On line Mendelian Inheritance in Man database and literature. Results: Non-PARK and PARK genes were involved in common functional modules related to autophagy, mitochondrial or lyso somal organization, catecholamine metabolic process, chemical synapse transmission, response to oxidative stress, neuronalapoptosis, regulation of cellular protein catabolic process, and vesicle-mediated transport in synapse. The hereditary parkinson ism proteins formed a single large network comprising 51 nodes, 83 edges, and three PPI pairs. The probability of degree distribu tion followed a power-law scaling behavior, with a degree exponent of 1.24 and a correlation coefficient of 0.92. LRRK2 was iden tified as a hub gene with the highest degree of betweenness centrality; its physical interaction enrichment score was 1.28, whichwas highly significant. Conclusion: Both PARK and non-PARK genes show high connectivity at the PPI and biological functional levels.
Abstract
Purpose: Hereditary parkinsonism genes consist of causative genes of familial Parkinson’s disease (PD) with a locus symbol prefix(PARK genes) and hereditary atypical parkinsonian disorders that present atypical features and limited responsiveness to levodopa(non-PARK genes). Although studies have shown that hereditary parkinsonism genes are related to idiopathic PD at the phenotyp ic, gene expression, and genomic levels, no study has systematically investigated connectivity among the proteins encoded bythese genes at the protein-protein interaction (PPI) level. Materials and Methods: Topological measurements and physical interaction enrichment were performed to assess PPI networksconstructed using some or all the proteins encoded by hereditary parkinsonism genes (n=96), which were curated using the On line Mendelian Inheritance in Man database and literature. Results: Non-PARK and PARK genes were involved in common functional modules related to autophagy, mitochondrial or lyso somal organization, catecholamine metabolic process, chemical synapse transmission, response to oxidative stress, neuronalapoptosis, regulation of cellular protein catabolic process, and vesicle-mediated transport in synapse. The hereditary parkinson ism proteins formed a single large network comprising 51 nodes, 83 edges, and three PPI pairs. The probability of degree distribu tion followed a power-law scaling behavior, with a degree exponent of 1.24 and a correlation coefficient of 0.92. LRRK2 was iden tified as a hub gene with the highest degree of betweenness centrality; its physical interaction enrichment score was 1.28, whichwas highly significant. Conclusion: Both PARK and non-PARK genes show high connectivity at the PPI and biological functional levels.
참고문헌 (40)
- Blauwendraat C, "The genetic architecture of Parkinson’s disease", Lancet Neurol, 19, pp.170~178 (2020)
- Kim YJ, "Dysregulation of the causative genes for hereditary parkinsonism in the midbrain in Parkinson’s disease", Mov Disord, 32, pp.1211~1220 (2017)
- Phung DM, "Meta-analysis of differentially expressed genes in the substantia nigra in Parkinson’s disease supports phenotype-specific transcriptome changes", Front Neurosci, 14, pp.596105~ (2020)
- Kim YJ, "The burden of rare damaging variants in hereditary atypical parkinsonism genes is increased in patients with Parkinson’s disease", Neurobiol Aging, 100, pp.118.e5~118.e13 (2021)
- Dittrich MT, "Identifying functional modules in protein-protein interaction networks : an integrated exact approach", Bioinformatics, 24, pp.i223~i231 (2008)
- Hao T, "Analyzing of molecular networks for human diseases and drug discovery", Curr Top Med Chem, 18, pp.1007~1014 (2018)
- Bandres-Ciga S, "Large-scale pathway specific polygenic risk and transcriptomic community network analysis identifies novel functional pathways in Parkinson disease", Acta Neuropathol, 140, pp.341~358 (2020)
- Ferrari R, "Stratification of candidate genes for Parkinson’s disease using weighted protein-protein interaction network analysis", BMC Genomics, 19, pp.452~ (2018)
- Siitonen A, "Finnish Parkinson’s disease study integrating proteinprotein interaction network data with exome sequencing analysis", Sci Rep, 9, pp.18865~ (2019)
- Goh KI, "The human disease network", Proc Natl Acad Sci U S A, 104, pp.8685~8690 (2007)
- Amberger JS, "OMIM.org: leveraging knowledge across phenotype-gene relationships", Nucleic Acids Res, 47(Database issue), pp.D1038~D1043 (2019)
- Fabiani G, "99mTc-TRODAT-1 SPECT showing dopaminergic deficiency in a patient with spinocerebellar ataxia type 10 and parkinsonism", Mov Disord Clin Pract, 6, pp.85~87 (2019)
- Nalls MA, "Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease : a meta-analysis of genome-wide association studies", Lancet Neurol, 18, pp.1091~1102 (2019)
- Andrews SJ, "Interpretation of risk loci from genome-wide association studies of Alzheimer’s disease", Lancet Neurol, 19, pp.326~335 (2020)
- Sjöstedt E, "An atlas of the protein-coding genes in the human, pig, and mouse brain", Science, 367, pp.eaay5947~ (2020)
- Raudvere U, "g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update)", Nucleic Acids Res, (Web server issue), pp.W191~W198 (2019)
- Orchard S, "The MIntAct project--IntAct as a common curation platform for 11 molecular interaction databases", Nucleic Acids Res, 42(Database issue), pp.D358~D363 (2014)
- Kerrien S, "The IntAct molecular interaction database in 2012", Nucleic Acids Res, 40(Database issue), pp.D841~D846 (2012)
- Barabási AL, "Network biology : understanding the cell’s functional organization", Nat Rev Genet, 5, pp.101~113 (2004)
- Ran J, "Construction and analysis of the protein-protein interaction network related to essential hypertension", BMC Syst Biol, 7, pp.32~ (2013)
- Watts DJ, "Collective dynamics of ‘small-world’ networks", Nature, 393, pp.440~442 (1998)
- Sama IE, "Measuring the physical cohesiveness of proteins using physical interaction enrichment", Bioinformatics, 26, pp.2737~2743 (2010)
- Nafis S, "Apoptosis regulatory protein-protein interaction demonstrates hierarchical scale-free fractal network", Brief Bioinform, 16, pp.675~699 (2015)
- Goñi J, "A computational analysis of proteinprotein interaction networks in neurodegenerative diseases", BMC Syst Biol, 2, pp.52~ (2008)
- Gan-Or Z, "The emerging role of SMPD1 mutations in Parkinson’s disease : implications for future studies", Parkinsonism Relat Disord, 21, pp.1294~1295 (2015)
- Mencacci NE, "Parkinson’s disease genomics consortium and UCL-exomes consortium. Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers", Brain, 137(Pt 9), pp.2480~2492 (2014)
- Sidransky E, "Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease", N Engl J Med, 361, pp.1651~1661 (2009)
- Gibb WR, "Idiopathic Parkinson’s disease and the Lewy body disorders", Neuropathol Appl Neurobiol, 12, pp.223~234 (1986)
- Hartig MB, "Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation", Am J Hum Genet, 89, pp.543~550 (2011)
- Schneider SA, "Neuropathology of genetic synucleinopathies with parkinsonism : review of the literature", Mov Disord, 32, pp.1504~1523 (2017)
- Takao M, "Spinocerebellar ataxia type 2 is associated with Parkinsonism and Lewy body pathology", BMJ Case Rep, 2011, pp.bcr0120113~ (2011)
- Wilson GR, "Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with α-synuclein pathology", Am J Hum Genet, 95, pp.729~735 (2014)
- Li YI, "Prioritizing Parkinson’s disease genes using population-scale transcriptomic data", Nat Commun, 10, pp.994~ (2019)
- Gallagher MD, "The post-GWAS era : from association to function", Am J Hum Genet, 102, pp.717~730 (2018)
- Ashtiani M, "A systematic survey of centrality measures for protein-protein interaction networks", BMC Syst Biol, 12, pp.80~ (2018)
- Csermely P, "Structure and dynamics of molecular networks : a novel paradigm of drug discovery : a comprehensive review", Pharmacol Ther, 138, pp.333~408 (2013)
- Salcedo-Arellano MJ, "Fragile X syndrome and associated disorders : clinical aspects and pathology", Neurobiol Dis, 136, pp.104740~ (2020)
- Tan Y, "Loss of fragile X mental retardation protein precedes Lewy pathology in Parkinson’s disease", Acta Neuropathol, 139, pp.319~345 (2020)
- Synofzik M, "Overcoming the divide between ataxias and spastic paraplegias : shared phenotypes, genes, and pathways", Mov Disord, 32, pp.332~345 (2017)
- Eidhof I, "Integrative network and brain expression analysis reveals mechanistic modules in ataxia", J Med Genet, 56, pp.283~292 (2019)