Top

Published in:

02-02-2024 | Atypical Parkinsonism | Original Article

Identification of metabolic pathways and key genes associated with atypical parkinsonism using a systems biology approach

Authors: Amanda Pasqualotto, Vinícius da Silva, Felipe Mateus Pellenz, Artur Francisco Schumacher Schuh, Ida Vanessa Doederlein Schwartz, Marina Siebert

Published in: Metabolic Brain Disease | Issue 4/2024

Abstract

Atypical parkinsonism (AP) is a group of complex neurodegenerative disorders with marked clinical and pathophysiological heterogeneity. The use of systems biology tools may contribute to the characterization of hub-bottleneck genes, and the identification of its biological pathways to broaden the understanding of the bases of these disorders. A systematic search was performed on the DisGeNET database, which integrates data from expert curated repositories, GWAS catalogues, animal models and the scientific literature. The tools STRING 11.0 and Cytoscape 3.8.2 were used for analysis of protein-protein interaction (PPI) network. The PPI network topography analyses were performed using the CytoHubba 0.1 plugin for Cytoscape. The hub and bottleneck genes were inserted into 4 different sets on the InteractiveVenn. Additional functional enrichment analyses were performed to identify Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and gene ontology for a described set of genes. The systematic search in the DisGeNET database identified 485 genes involved with Atypical Parkinsonism. Superimposing these genes, we detected a total of 31 hub-bottleneck genes. Moreover, our functional enrichment analyses demonstrated the involvement of these hub-bottleneck genes in 3 major KEGG pathways. We identified 31 highly interconnected hub-bottleneck genes through a systems biology approach, which may play a key role in the pathogenesis of atypical parkinsonism. The functional enrichment analyses showed that these genes are involved in several biological processes and pathways, such as the glial cell development, glial cell activation and cognition, pathways were related to Alzheimer disease and Parkinson disease. As a hypothesis, we highlight as possible key genes for AP the MAPT (microtubule associated protein tau), APOE (apolipoprotein E), SNCA (synuclein alpha) and APP (amyloid beta precursor protein) genes.

Available only for authorised users

Allen SJ, Watson JJ, Shoemark DK et al (2013) GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol Ther 138:155–175. https://doi.org/10.1016/j.pharmthera.2013.01.004CrossRefPubMed

Arendt T, Stieler JT, Holzer M (2016) Tau and tauopathies. Brain Res Bull 126:238–292. https://doi.org/10.1016/j.brainresbull.2016.08.018CrossRefPubMed

Aydin D, Weyer SW, Müller UC (2012) Functions of the APP gene family in the nervous system: insights from mouse models. Exp Brain Res 217:423–434. https://doi.org/10.1007/s00221-011-2861-2CrossRefPubMed

Bindea G, Mlecnik B, Hackl H et al (2009) ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics 25:1091–1093. https://doi.org/10.1093/bioinformatics/btp101CrossRefPubMedPubMedCentral

Booth HDE, Hirst WD, Wade-Martins R (2017) The role of astrocyte dysfunction in Parkinson’s Disease Pathogenesis. Trends Neurosci 40:358–370. https://doi.org/10.1016/j.tins.2017.04.001CrossRefPubMedPubMedCentral

Bras J, Guerreiro R, Darwent L et al (2014) Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies. Hum Mol Genet 23:6139–6146. https://doi.org/10.1093/hmg/ddu334CrossRefPubMedPubMedCentral

Brown RC, Lockwood AH, Sonawane BR (2005) Neurodegenerative diseases: an overview of environmental risk factors. Environ Health Perspect 113:1250–1256. https://doi.org/10.1289/ehp.7567CrossRefPubMedPubMedCentral

Caillet-Boudin ML, Buée L, Sergeant N, Lefebvre B (2015) Regulation of human MAPT gene expression. Mol Neurodegener 10:1–14. https://doi.org/10.1186/s13024-015-0025-8CrossRef

Chen Y, Cao B, Yang J et al (2015) Analysis and meta-analysis of five polymorphisms of the LINGO1 and LINGO2 genes in Parkinson’s disease and multiple system atrophy in a Chinese population. J Neurol 262:2478–2483. https://doi.org/10.1007/s00415-015-7870-9CrossRefPubMed

Chia R, Sabir MS, Bandres-Ciga S et al (2021) Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture. Nat Genet 53:294–303. https://doi.org/10.1038/s41588-021-00785-3CrossRefPubMedPubMedCentral

Dai L, Zou L, Meng L et al (2021) Cholesterol metabolism in neurodegenerative diseases: Molecular mechanisms and therapeutic targets. Mol Neurobiol 58:2183–2201. https://doi.org/10.1007/s12035-020-02232-6CrossRefPubMed

Deutschländer AB, Ross OA, Dickson DW, Wszolek ZK (2018) Atypical parkinsonian syndromes: a general neurologist’s perspective. Eur J Neurol

Devi G (2023) The tauopathies. Handb Clin Neurol 196:251–265. https://doi.org/10.1016/B978-0-323-98817-9.00015-6CrossRefPubMed

Dickson DW, Bergeron C, Chin SS et al (2002) Office of rare diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol 61. https://doi.org/10.1093/jnen/61.11.935

Dietschy JM, Turley SD (2004) Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res

Diez-Fairen M, Alvarez Jerez P, Berghausen J, Bandres-Ciga S (2021) The Genetic Landscape of parkinsonism-related Dystonias and atypical parkinsonism-related syndromes. Int J Mol Sci 22. https://doi.org/10.3390/ijms22158100

Don AS, Hsiao J-HT, Bleasel JM et al (2014) Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy. Acta Neuropathol Commun 2:150. https://doi.org/10.1186/s40478-014-0150-6CrossRefPubMedPubMedCentral

Fabbrini G, Fabbrini A, Suppa A (2019) Progressive supranuclear palsy, multiple system atrophy and corticobasal degeneration. Handb Clin Neurol 165:155–177. https://doi.org/10.1016/B978-0-444-64012-3.00009-5CrossRefPubMed

Fellner L, Stefanova N (2013) The role of glia in α-synucleinopathies. Mol Neurobiol 47:575–586. https://doi.org/10.1007/s12035-012-8340-3CrossRefPubMed

Foguem C, Manckoundia P (2018) Lewy Body Disease: clinical and pathological overlap syndrome between synucleinopathies (Parkinson Disease) and tauopathies (Alzheimer Disease). Curr Neurol Neurosci Rep 18

Giagkou N, Stamelou M (2018) Therapeutic management of the overlapping syndromes of atypical parkinsonism. CNS Drugs

Harris MA, Clark JI, Ireland A et al (2006) The gene ontology (GO) project in 2006. Nucleic Acids Res 34:D322–D326. https://doi.org/10.1093/nar/gkj021CrossRef

Heberle H, Meirelles VG, da Silva FR et al (2015) InteractiVenn: a web-based tool for the analysis of sets through Venn diagrams. BMC Bioinformatics 16:1–7. https://doi.org/10.1186/s12859-015-0611-3CrossRef

Heckman MG, Kasanuki K, Brennan RR et al (2019) Association of MAPT H1 subhaplotypes with neuropathology of lewy body disease. Mov Disord 34:1325–1332. https://doi.org/10.1002/mds.27773CrossRefPubMedPubMedCentral

Höglinger GU, Melhem NM, Dickson DW et al (2011) Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 43:699–705. https://doi.org/10.1038/ng.859CrossRefPubMedPubMedCentral

Höglinger GU, Respondek G, Stamelou M et al (2017) Clinical diagnosis of progressive supranuclear palsy: the movement disorder society criteria. Mov Disord. https://doi.org/10.1002/mds.26987CrossRefPubMedPubMedCentral

Holmberg B, Rosengren L, Karlsson J-E, Johnels B (1998) Increased cerebrospinal fluid levels of neurofilament protein in progressive supranuclear palsy and multiple-system atrophy compared with Parkinson’s disease. Mov Disord 13:70–77. https://doi.org/10.1002/mds.870130116CrossRefPubMed

Jellinger KA (2018) Multiple system atrophy: an oligodendroglioneural Synucleinopathy1. J Alzheimers Dis 62:1141–1179. https://doi.org/10.3233/JAD-170397CrossRefPubMedPubMedCentral

Jellinger KA, Wenning GK (2016) Multiple system atrophy: pathogenic mechanisms and biomarkers. J Neural Transm (Vienna) 123:555–572. https://doi.org/10.1007/s00702-016-1545-2CrossRefPubMed

Kim EK, Choi EJ (2010) Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta Mol Basis Dis 1802:396–405. https://doi.org/10.1016/j.bbadis.2009.12.009CrossRef

Kim SS, Moon KR, Choi HJ (2011) Interference of alpha-synuclein with cAMP/PKA-dependent CREB signaling for tyrosine hydroxylase gene expression in SK-N-BE(2)C cells. Arch Pharm Res 34:837–845. https://doi.org/10.1007/s12272-011-0518-0CrossRefPubMed

Kouri N, Ross OA, Dombroski B et al (2015) Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy. Nat Commun 6:1–7. https://doi.org/10.1038/ncomms8247CrossRef

Lill CM (2016) Genetics of Parkinson’s disease. Mol Cell Probes

Lim Y, Kehm VM, Lee EB et al (2011) Α-Syn suppression reverses synaptic and memory defects in a mouse model of Dementia with Lewy Bodies. J Neurosci 31:10076–10087. https://doi.org/10.1523/JNEUROSCI.0618-11.2011CrossRefPubMedPubMedCentral

Lim EW, Aarsland D, Ffytche D et al (2019) Amyloid-β and Parkinson’s disease. J Neurol 266:2605–2619. https://doi.org/10.1007/s00415-018-9100-8CrossRefPubMed

McKeith IG, Boeve BF, Dickson DW et al (2017) Diagnosis and management of dementia with Lewy bodies. Neurology 89:88–100. https://doi.org/10.1212/WNL.0000000000004058

Melissa J, Armstrong et al (2013) Criteria for the diagnosis of corticobasal degeneration. Neurology 67:513–523. https://doi.org/10.1212/WNL.0b013e31827f0fd1.CrossRef

Minoru Kanehisa and Susumu Goto (2000) KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28:27–30CrossRef

Miryala SK, Anbarasu A, Ramaiah S (2018) Discerning molecular interactions: A comprehensive review on biomolecular interaction databases and network analysis tools. Gene

Mitsui J, Matsukawa T, Sasaki H et al (2015) Variants associated with gaucher disease in multiple system atrophy. Ann Clin Transl Neurol. https://doi.org/10.1002/acn3.185CrossRefPubMedPubMedCentral

Pang E, Hao Y, Sun Y, Lin K (2016) Differential variation patterns between hubs and bottlenecks in human protein-protein interaction networks. BMC Evol Biol. https://doi.org/10.1186/s12862-016-0840-8CrossRefPubMedPubMedCentral

Piñero J, Bravo Á, Queralt-Rosinach N et al (2017a) DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res 45:D833–D839. https://doi.org/10.1093/nar/gkw943CrossRefPubMed

Piñero J, Bravo Á, Queralt-Rosinach N et al (2017b) DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res. https://doi.org/10.1093/nar/gkw943CrossRefPubMed

Polymeropoulos MH, Lavedan C, Leroy E et al (1997) Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Sci (1979) 276:2045–2047. https://doi.org/10.1126/science.276.5321.2045

Povey S, Lovering R, Bruford E et al (2001) The HUGO Gene Nomenclature Committee (HGNC). Hum Genet 109:678–680. https://doi.org/10.1007/s00439-001-0615-0CrossRefPubMed

Rahmati S, Abovsky M, Pastrello C, Jurisica I (2017) PathDIP: an annotated resource for known and predicted human gene-pathway associations and pathway enrichment analysis. Nucleic Acids Res 45:D419–D426. https://doi.org/10.1093/nar/gkw1082CrossRefPubMed

Rösler TW, Tayaranian Marvian A, Brendel M et al (2019) Four-repeat tauopathies. Prog Neurobiol 180:101644. https://doi.org/10.1016/j.pneurobio.2019.101644CrossRefPubMed

Sabir MS, Blauwendraat C, Ahmed S et al (2019) Assessment of APOE in atypical parkinsonism syndromes. Neurobiol Dis 127:142–146. https://doi.org/10.1016/j.nbd.2019.02.016CrossRefPubMedPubMedCentral

Sanford AM (2018) Lewy Body Dementia. Clin Geriatr Med 34:603–615. https://doi.org/10.1016/j.cger.2018.06.007CrossRefPubMed

Sawa A, Amano N, Yamada N et al (1997) Apolipoprotein E in progressive supranuclear palsy in Japan. Mol Psychiatry 2:341–342. https://doi.org/10.1038/sj.mp.4000285CrossRefPubMed

Scholz SW, Bras J (2015) Genetics underlying atypical parkinsonism and related neurodegenerative disorders. Int J Mol Sci

Scholz SW, Houlden H, Schulte C et al (2009) SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol 65:610–614. https://doi.org/10.1002/ana.21685CrossRefPubMedPubMedCentral

Serrano-Pozo A, Das S, Hyman BT (2021) APOE and Alzheimer’s disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol 20:68–80. https://doi.org/10.1016/S1474-4422(20)30412-9CrossRefPubMedPubMedCentral

Shannon P, Markiel A, Ozier O et al (2003) Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504. https://doi.org/10.1101/gr.1239303CrossRefPubMedPubMedCentral

Sidransky E, Nalls MA, Aasly JO et al (2009) Multicenter Analysis of glucocerebrosidase mutations in Parkinson’s Disease. N Engl J Med. https://doi.org/10.1056/NEJMoa0901281CrossRefPubMedPubMedCentral

Stamelou M, Respondek G, Giagkou N et al (2021) Evolving concepts in progressive supranuclear palsy and other 4-repeat tauopathies. Nat Rev Neurol 17:601–620. https://doi.org/10.1038/s41582-021-00541-5CrossRefPubMed

Stefanis L (2012) α-Synuclein in Parkinson’s disease. Cold Spring Harb Perspect Med 2:a009399. https://doi.org/10.1101/cshperspect.a009399CrossRefPubMedPubMedCentral

Stefanova N, Reindl M, Neumann M et al (2007) Microglial activation mediates neurodegeneration related to oligodendroglial alpha-synucleinopathy: implications for multiple system atrophy. Mov Disord 22:2196–2203. https://doi.org/10.1002/mds.21671CrossRefPubMed

Strang KH, Golde TE, Giasson BI (2019) MAPT mutations, tauopathy, and mechanisms of neurodegeneration. Lab Invest 99:912–928. https://doi.org/10.1038/s41374-019-0197-xCrossRefPubMedPubMedCentral

Szklarczyk D, Gable AL, Lyon D et al (2019) STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 47:D607–D613. https://doi.org/10.1093/nar/gky1131CrossRefPubMed

Tavassoly I, Goldfarb J, Iyengar R (2018) Systems biology primer: the basic methods and approaches. Essays Biochem 62:487–500. https://doi.org/10.1042/EBC20180003CrossRefPubMed

Ubhi K, Lee PH, Adame A et al (2009) Mitochondrial inhibitor 3-nitroproprionic acid enhances oxidative modification of alpha-synuclein in a transgenic mouse model of multiple system atrophy. J Neurosci Res 87:2728–2739. https://doi.org/10.1002/jnr.22089CrossRefPubMedPubMedCentral

Vance JE (2012) Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases. DMM Disease Models and Mechanisms

Vidal M (2009) A unifying view of 21st century systems biology. FEBS Lett

Wenning GK, Stankovic I, Vignatelli L et al (2022) The Movement Disorder Society Criteria for the diagnosis of multiple system atrophy. Mov Disord 37:1131–1148CrossRefPubMedPubMedCentral

Xu W, Tan L, Yu JT (2015) The link between the SNCA gene and parkinsonism. Neurobiol Aging 36:1505–1518. https://doi.org/10.1016/j.neurobiolaging.2014.10.042CrossRefPubMed

Zhao N, Liu C-C, Van Ingelgom AJ et al (2018) APOE ε2 is associated with increased tau pathology in primary tauopathy. Nat Commun 9:4388. https://doi.org/10.1038/s41467-018-06783-0CrossRefPubMedPubMedCentral

Title: Identification of metabolic pathways and key genes associated with atypical parkinsonism using a systems biology approach
Authors: Amanda Pasqualotto
Vinícius da Silva
Felipe Mateus Pellenz
Artur Francisco Schumacher Schuh
Ida Vanessa Doederlein Schwartz
Marina Siebert
Publication date: 02-02-2024
Publisher: Springer US
Keywords: Atypical Parkinsonism
Progressive Supranuclear Palsy
Dementia
Dementia
Parkinson's Disease
Published in: Metabolic Brain Disease / Issue 4/2024
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-024-01342-7

2024 ASCO Annual Meeting

Springer Medicine

Identification of metabolic pathways and key genes associated with atypical parkinsonism using a systems biology approach

Abstract

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2024

Molecular and in silico investigation of a novel ECHS1 gene mutation in a consanguine family with short-chain enoyl-CoA hydratase deficiency and Mt-DNA depletion: effect on trimer assembly and catalytic activity

Hesperidin counteracts chlorpyrifos-induced neurotoxicity by regulating oxidative stress, inflammation, and apoptosis in rats

Chitosan/PLA-loaded Magnesium oxide nanocomposite to attenuate oxidative stress, neuroinflammation and neurotoxicity in rat models of Alzheimer's disease

Therapeutic efficacy and pharmacological mechanism of Yindan Xinnaotong soft capsule on acute ischemic stroke: a meta-analysis and network pharmacology analysis

Considerations for Chinese tolerable upper intake level for selenium

A computational approach to analyzing the functional and structural impacts of Tripeptidyl-Peptidase 1 missense mutations in neuronal ceroid lipofuscinosis