Gene networks and metabolomic screening analysis revealed specific pathways of amino acid and acylcarnitine profile alterations in blood plasma of patients with Parkinson’s disease and vascular parkinsonism

Parkinson’s disease (PD) and vascular parkinsonism (VP) are characterized by similar neurological syndromes but differ in pathogenesis, morphology, and therapeutic approaches. The molecular genetic mechanisms of these pathologies are multifactorial and involve multiple biological processes. To comprehensively analyze the pathophysiology of PD and VP, the methods of systems biology and gene network reconstruction are essential. In the current study, we performed metabolomic screening of amino acids and acylcarnitines in blood plasma of three groups of subjects: PD patients, VP patients and the control group. Comparative statistical analysis of the metabolic profiles identified significantly altered metabolites in the PD and the VP group. To identify potential mechanisms of amino acid and acylcarnitine metabolism disorders in PD and VP, regulatory gene networks were reconstructed using ANDSystem, a cognitive system. Regulatory pathways to the enzymes converting significant metabolites were found from PD­specific genetic markers, VP­specific genetic markers, and the group of genetic markers common to the two diseases. Comparative analysis of molecular genetic pathways in gene networks allowed us to identify both specific and non­specific molecular mechanisms associated with changes in the metabolomic profile in PD and VP. Regulatory pathways with potentially impaired function in these pathologies were discovered. The regulatory pathways to the enzymes ALDH2, BCAT1, AL1B1, and UD11 were found to be specific for PD, while the pathways regulating OCTC, FURIN, and S22A6 were specific for VP. The pathways regulating BCAT2, ODPB and P4HA1 were associated with genetic markers common to both diseases. The results obtained deepen the understanding of pathological processes in PD and VP and can be used for application of diagnostic systems based on the evaluation of the amino acids and acylcarnitines profile in blood plasma of patients with PD and VP.

1. Alexander G.E. Biology of Parkinson’s disease: pathogenesis and pathophysiology of a multisystem neurodegenerative disorder. Dialogues Clin. Neurosci. 2004;6(3):259-280. doi 10.31887/DCNS.2004.6.3/galexander

2. Ashby E.L., Kierzkowska M., Hull J., Kehoe P.G., Hutson S.M., Conway M.E. Altered expression of human mitochondrial branched chain aminotransferase in dementia with Lewy bodies and vascular dementia. Neurochem. Res. 2017;42(1):306-319. doi 10.1007/s11064-016-1855-7

3. Binder H., Wirth H., Arakelyan A., Lembcke K., Tiys E.S., Ivanisenko V.A., Kolchanov N.A., Kononikhin A., Popov I., Nikolaev E.N., Pastushkova L.K., Larina I.M. Time-course human urine proteomics in space-flight simulation experiments. BMC Genomics. 2014; 15(S12):S2. doi 10.1186/1471-2164-15-S12-S2

4. Børglum A.D., Flint T., Hansen L.L., Kruse T.A. Refined localization of the pyruvate dehydrogenase E1α gene (PDHA1) by linkage analysis. Hum. Genet. 1996;99(1):80-82. doi 10.1007/s004390050315

5. Braak H., Tredici K.D., Rüb U., De Vos R.A.I., Jansen Steur E.N.H., Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging. 2003;24(2):197-211. doi 10.1016/S0197-4580(02)00065-9

6. Bragina E.Yu., Tiys E.S., Freidin M.B., Koneva L.A., Demenkov P.S., Ivanisenko V.A., Kolchanov N.A., Puzyrev V.P. Insights into pathophysiology of dystropy through the analysis of gene networks: an example of bronchial asthma and tuberculosis. Immunogenetics. 2014;66(7-8):457-465. doi 10.1007/s00251-014-0786-1

7. Bragina E.Yu., Tiys E.S., Rudko A.A., Ivanisenko V.A., Freidin M.B. Novel tuberculosis susceptibility candidate genes revealed by the reconstruction and analysis of associative networks. Infect. Genet. Evol. 2016;46:118-123. doi 10.1016/j.meegid.2016.10.030

8. Bragina E.Yu., Gomboeva D.E., Saik O.V., Ivanisenko V.A., Freidin M.B., Nazarenko M.S., Puzyrev V.P. Apoptosis genes as a key to identification of inverse comorbidity of Huntington’s disease and cancer. Int. J. Mol. Sci. 2023;24(11):9385. doi 10.3390/ijms24119385

9. Che Mohd Nassir C.M.N., Damodaran T., Yusof S.R., Norazit A., Chilla G., Huen I., Kn B.P., Mohamed Ibrahim N., Mustapha M. Aberrant neurogliovascular unit dynamics in cerebral small vessel disease: a rheological clue to vascular Parkinsonism. Pharmaceutics. 2021;13(8):1207. doi 10.3390/pharmaceutics13081207

10. Chen C.-H., Joshi A.U., Mochly-Rosen D. The role of mitochondrial aldehyde dehydrogenase 2 (ALDH2) in neuropathology and neurodegeneration. Acta Neurol. Taiwan. 2016;25(4)(4):111-123

11. Chen Y., Liu Q., Liu J., Wei P., Li B., Wang N., Liu Z., Wang Z. Revealing the modular similarities and differences among Alzheimer’s disease, vascular dementia, and Parkinson’s disease in genomic networks. Neuromol. Med. 2022;24(2):125-138. doi 10.1007/s12017-021-08670-2

12. Chen Y.-F., Tseng Y.-L., Lan M.-Y., Lai S.-L., Su C.-S., Liu J.-S., Chang Y.-Y. The relationship of leukoaraiosis and the clinical severity of vascular Parkinsonism. J. Neurol. Sci. 2014;346(1-2):255-259. doi 10.1016/j.jns.2014.09.002

13. Chiu C.-C., Yeh T.-H., Lai S.-C., Wu-Chou Y.-H., Chen C.-H., Mochly-Rosen D., Huang Y.-C., Chen Y.-J., Chen C.-L., Chang Y.-M., Wang H.-L., Lu C.-S. Neuroprotective effects of aldehyde dehydrogenase 2 activation in rotenone-induced cellular and animal models of parkinsonism. Exp. Neurol. 2015;263:244-253. doi 10.1016/j.expneurol.2014.09.016

14. Dalangin R., Kim A., Campbell R.E. The role of amino acids in neurotransmission and fluorescent tools for their detection. Int. J. Mol. Sci. 2020;21(17):6197. doi 10.3390/ijms21176197

15. De Holanda Paranhos L., Magalhães R.S.S., De Araújo Brasil A., Neto J.R.M., Ribeiro G.D., Queiroz D.D., Dos Santos V.M., Eleutherio E.C.A. The familial amyotrophic lateral sclerosis-associated A4V SOD1 mutant is not able to regulate aerobic glycolysis. Biochim. Biophys. Acta Gen. Subjt. 2024;1868(8):130634. doi 10.1016/j.bbagen.2024.130634

16. Demenkov P.S., Ivanisenko T.V., Kolchanov N.A., Ivanisenko V.A. ANDVisio: a new tool for graphic visualization and analysis of literature mined associative gene networks in the ANDSystem. In Silico Biol. 2012;11(3-4):149-161. doi 10.3233/ISB-2012-0449

17. Dimas P., Montani L., Pereira J.A., Moreno D., Trötzmüller M., Gerber J., Semenkovich C.F., Köfeler H.C., Suter U. CNS myelination and remyelination depend on fatty acid synthesis by oligodendrocytes. eLife. 2019;8:e44702. doi 10.7554/eLife.44702

18. Ferrari M., Martignoni E., Blandini F., Riboldazzi G., Bono G., Marino F., Cosentino M. Association of UDP-glucuronosyltransferase 1A9 polymorphisms with adverse reactions to catechol-O-methyltransferase inhibitors in Parkinson’s disease patients. Eur. J. Clin. Pharmacol. 2012;68(11):1493-1499. doi 10.1007/s00228-012-1281-y

19. George G., Singh S., Lokappa S.B., Varkey J. Gene co-expression network analysis for identifying genetic markers in Parkinson’s disease – a three-way comparative approach. Genomics. 2019a;111(4): 819-830. doi 10.1016/j.ygeno.2018.05.005

20. George G., Valiya Parambath S., Lokappa S.B., Varkey J. Construction of Parkinson’s disease marker-based weighted protein-protein interaction network for prioritization of co-expressed genes. Gene. 2019b;697:67-77. doi 10.1016/j.gene.2019.02.026

21. Grassi D., Howard S., Zhou M., Diaz-Perez N., Urban N.T., Guerrero-Given D., Kamasawa N., Volpicelli-Daley L.A., LoGrasso P., Lasmézas C.I. Identification of a highly neurotoxic α-synuclein species inducing mitochondrial damage and mitophagy in Parkinson’s disease. Proc. Natl. Acad. Sci. USA. 2018;115(11):E2634-E2643. doi 10.1073/pnas.1713849115

22. Grünblatt E., Riederer P. Aldehyde dehydrogenase (ALDH) in Alzheimer’s and Parkinson’s disease. J. Neural. Transm. 2016;123(2): 83-90. doi 10.1007/s00702-014-1320-1

23. Ivanisenko T.V., Saik O.V., Demenkov P.S., Ivanisenko N.V., Savostianov A.N., Ivanisenko V.A. ANDDigest: a new web-based module of ANDSystem for the search of knowledge in the scientific literature. BMC Bioinformatics. 2020;21(S11):228. doi 10.1186/s12859-020-03557-8

24. Ivanisenko T.V., Demenkov P.S., Kolchanov N.A., Ivanisenko V.A. The new version of the ANDDigest tool with improved ai-based short names recognition. Int. J. Mol. Sci. 2022;23(23):14934. doi 10.3390/ijms232314934

25. Ivanisenko V.A., Saik O.V., Ivanisenko N.V., Tiys E.S., Ivanisenko T.V., Demenkov P.S., Kolchanov N.A. ANDSystem: an Associative Network Discovery System for automated literature mining in the field of biology. BMC Syst. Biol. 2015;9(Suppl.2):S2. doi 10.1186/1752-0509-9-S2-S2

26. Ivanisenko V.A., Demenkov P.S., Ivanisenko T.V., Mishchenko E.L., Saik O.V. A new version of the ANDSystem tool for automatic extraction of knowledge from scientific publications with expanded functionality for reconstruction of associative gene networks by considering tissue-specific gene expression. BMC Bioinformatics. 2019; 20(S1):34. doi 10.1186/s12859-018-2567-6

27. Ivanisenko V.A., Gaisler E.V., Basov N.V., Rogachev A.D., Cheresiz S.V., Ivanisenko T.V., Demenkov P.S., Mishchenko E.L., Khripko O.P., Khripko Yu.I., Voevoda S.M., Karpenko T.N., Velichko A.J., Voevoda M.I., Kolchanov N.A., Pokrovsky A.G. Plasma metabolomics and gene regulatory networks analysis reveal the role of nonstructural SARS-CoV-2 viral proteins in metabolic dysregulation in COVID-19 patients. Sci. Rep. 2022;12(1):19977. doi 10.1038/s41598-022-24170-0

28. Ivanisenko V.A., Basov N.V., Makarova A.A., Venzel A.S., Rogachev A.D., Demenkov P.S., Ivanisenko T.V., Kleshchev M.A., Gaisler E.V., Moroz G.B., Plesko V.V., Sotnikova Y.S., Patrushev Y.V., Lomivorotov V.V., Kolchanov N.A., Pokrovsky A.G. Gene networks for use in metabolomic data analysis of blood plasma from patients with postoperative delirium. Vavilov J. Genet. Breed. 2023;27(7): 768-775. doi 10.18699/VJGB-23-89

29. Jones L.L., McDonald D.A., Borum P.R. Acylcarnitines: role in brain. Prog. Lipid Res. 2010;49(1):61-75. doi 10.1016/j.plipres.2009.08.004

30. Kanehisa M. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27-30. doi 10.1093/nar/28.1.27

31. Kasakin M.F., Rogachev A.D., Predtechenskaya E.V., Zaigraev V.J., Koval V.V., Pokrovsky A.G. Targeted metabolomics approach for identification of relapsing-remitting multiple sclerosis markers and evaluation of diagnostic models. Med. Chem. Commun. 2019;10(10): 1803-1809. doi 10.1039/c9md00253g

32. Korczyn A.D. Vascular Parkinsonism – characteristics, pathogenesis and treatment. Nat. Rev. Neurol. 2015;11(6):319-326. doi 10.1038/nrneurol.2015.61

33. Larina I.M., Pastushkova L.Kh., Tiys E.S., Kireev K.S., Kononikhin A.S., Starodubtseva N.L., Popov I.A., Custaud M.-A., Dobrokhotov I.V., Nikolaev E.N., Kolchanov N.A., Ivanisenko V.A. Permanent proteins in the urine of healthy humans during the Mars-500 experiment. J. Bioinform. Comput. Biol. 2015;13(01):1540001. doi 10.1142/S0219720015400016

34. Levin O.S., Bogolepova A.N., Lobzin V.Yu. General mechanisms of the pathogenesis of neurodenerative and cerebrovascular diseases and the possibilities of their correction. Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova = S.S. Korsakov Journal of Neurology and Psychiatry. 2022;122(5):11-16. doi 10.17116/jnevro202212205111 (in Russian)

35. Lin L., Tao J.-P., Li M., Peng J., Zhou C., Ouyang J., Si Y.-Y. Mechanism of ALDH2 improves the neuronal damage caused by hypoxia/reoxygenation. Eur. Rev. Med. Pharmacol. Sci. 2022;26(8):2712-2720. doi 10.26355/eurrev_202204_28601

36. Maksoud E., Liao E.H., Haghighi A.P. A neuron-glial trans-signaling cascade mediates LRRK2-induced neurodegeneration. Cell Rep. 2019;26(7):1774-1786.e4. doi 10.1016/j.celrep.2019.01.077

37. Mercatelli D., Scalambra L., Triboli L., Ray F., Giorgi F.M. Gene regulatory network inference resources: a practical overview. Biochim. Biophys. Acta Gene Regul. Mech. 2020;1863(6):194430. doi 10.1016/j.bbagrm.2019.194430

38. Michel T.M., Käsbauer L., Gsell W., Jecel J., Sheldrick A.J., Cortese M., Nickl-Jockschat T., Grünblatt E., Riederer P. Aldehyde dehydrogenase 2 in sporadic Parkinson’s disease. Parkinsonism Relat. Disord. 2014;20:S68-S72. doi 10.1016/S1353-8020(13)70018-X

39. Miki Y., Tanji K., Mori F., Kakita A., Takahashi H., Wakabayashi K. Alteration of mitochondrial protein PDHA1 in Lewy body disease and PARK14. Biochem. Biophys. Res. Commun. 2017;489(4):439-444. doi 10.1016/j.bbrc.2017.05.162

40. Mor D.E., Sohrabi S., Kaletsky R., Keyes W., Tartici A., Kalia V., Miller G.W., Murphy C.T. Metformin rescues Parkinson’s disease phenotypes caused by hyperactive mitochondria. Proc. Natl. Acad. Sci. USA. 2020;117(42):26438-26447. doi 10.1073/pnas.2009838117

41. Nalls M.A., Pankratz N., Lill C.M., Do C.B., Hernandez D.G., Saad M., DeStefano A.L., Kara E., Bras J., Sharma M., … Brice A., Scott W.K., Gasser T., Bertram L., Eriksson N., Foroud T., Singleton A.B. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat. Genet. 2014; 46(9):989-993. doi 10.1038/ng.3043

42. Narasimhan M., Schwartz R., Halliday G. Parkinsonism and cerebrovascular disease. J. Neurol. Sci. 2022;433:120011. doi 10.1016/j.jns.2021.120011

43. Narendra D.P., Jin S.M., Tanaka A., Suen D.-F., Gautier C.A., Shen J., Cookson M.R., Youle R.J. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 2010;8(1):e1000298. doi 10.1371/journal.pbio.1000298

44. Odongo R., Bellur O., Abdik E., Çakır T. Brain-wide transcriptomebased metabolic alterations in Parkinson’s disease: human inter-region and human-experimental model correlations. Mol. Omics. 2023; 19(7):522-537. doi 10.1039/D2MO00343K

45. Okui T., Iwashita M., Rogers M.A., Halu A., Atkins S.K., Kuraoka S., Abdelhamid I., Higashi H., Ramsaroop A., Aikawa M., Singh S.A., Aikawa E. CROT (Carnitine O-Octanoyltransferase) is a novel contributing factor in vascular calcification via promoting fatty acid metabolism and mitochondrial dysfunction. Arterioscler. Thromb. Vasc. Biol. 2021;41(2):755-768. doi 10.1161/ATVBAHA.120.315007

46. Ostrakhovitch E.A., Song E.-S., Macedo J.K.A., Gentry M.S., Quintero J.E., Van Horne C., Yamasaki T.R. Analysis of circulating metabolites to differentiate Parkinson’s disease and essential tremor. Neurosci. Lett. 2022;769:136428. doi10.1016/j.neulet.2021.136428

47. Pastushkova L.Kh., Kireev K.S., Kononikhin A.S., Tiys E.S., Popov I.A., Starodubtseva N.L., Dobrokhotov I.V., Ivanisenko V.A., Larina I.M., Kolchanov N.A., Nikolaev E.N. Detection of renal tissue and urinary tract proteins in the human urine after space flight. PLoS One. 2013;8(8):e71652. doi 10.1371/journal.pone.0071652

48. Pastushkova L.Kh., Kashirina D.N., Brzhozovskiy A.G., Kononikhin A.S., Tiys E.S., Ivanisenko V.A., Koloteva M.I., Nikolaev E.N., Larina I.M. Evaluation of cardiovascular system state by urine proteome after manned space flight. Acta Astronaut. 2019;160:594-600. doi 10.1016/j.actaastro.2019.02.015

49. Pavlú-Pereira H., Florindo C., Carvalho F., Tavares De Almeida I., Vicente J., Morais V., Rivera I. Evaluation of mitochondrial function on pyruvate dehydrogenase complex deficient patient-derived cell lines. Endocr. Metab. Immune Disord. Drug Targets. 2024;24(16):20. doi 10.2174/0118715303280072231004082458

50. Penney J., Tsurudome K., Liao E.H., Kauwe G., Gray L., Yanagiya A., Calderon M.R., Sonenberg N., Haghighi A.P. LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction. Nat. Commun. 2016;7(1):12188. doi 10.1038/ncomms12188

51. Rappaport N., Twik M., Nativ N., Stelzer G., Bahir I., Stein T.I., Safran M., Lancet D. MalaCards: a comprehensive automaticallymined database of human diseases. Curr. Protoc. Bioinformatics. 2014;47(1):1.24.1-19. doi 10.1002/0471250953.bi0124s47

52. Rocha E.M., De Miranda B., Sanders L.H. Alpha-synuclein: pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease. Neurobiol. Dis. 2018;109:249-257. doi 10.1016/j.nbd.2017.04.004

53. Rogachev A.D., Alemasov N.A., Ivanisenko V.A., Ivanisenko N.V., Gaisler E.V., Oleshko O.S., Cheresiz S.V., Mishinov S.V., Stupak V.V., Pokrovsky A.G. Correlation of metabolic profiles of plasma and cerebrospinal fluid of high-grade glioma patients. Metabolites. 2021;11(3):133. doi 10.3390/metabo11030133

54. Saik O.V., Ivanisenko T.V., Demenkov P.S., Ivanisenko V.A. Interactome of the hepatitis C virus: literature mining with ANDSystem. Virus Res. 2016;218:40-48. doi 10.1016/j.virusres.2015.12.003

55. Saik O.V., Demenkov P.S., Ivanisenko T.V., Bragina E.Yu., Freidin M.B., Dosenko V.E., Zolotareva O.I., Choynzonov E.L., Hofestaedt R., Ivanisenko V.A. Search for new candidate genes involved in the comorbidity of asthma and hypertension based on automatic analysis of scientific literature. J. Integr. Bioinform. 2018; 15(4):20180054. doi 10.1515/jib-2018-0054

56. Saik O.V., Nimaev V.V., Usmonov D.B., Demenkov P.S., Ivanisenko T.V., Lavrik I.N., Ivanisenko V.A. Prioritization of genes involved in endothelial cell apoptosis by their implication in lymphedema using an analysis of associative gene networks with ANDSystem. BMC Med. Genomics. 2019;12(S2):47. doi 10.1186/s12920-019-0492-9

57. Saiki S., Hatano T., Fujimaki M., Ishikawa K.-I., Mori A., Oji Y., Okuzumi A., Fukuhara T., Koinuma T., Imamichi Y., Nagumo M., Furuya N., Nojiri S., Amo T., Yamashiro K., Hattori N. Decreased long-chain acylcarnitines from insufficient β-oxidation as potential early diagnostic markers for Parkinson’s disease. Sci. Rep. 2017; 7(1):7328. doi 10.1038/s41598-017-06767-y

58. Schlaepfer I.R., Joshi M. CPT1A-mediated fat oxidation, mechanisms, and therapeutic potential. Endocrinology. 2020;161(2):bqz046. doi 10.1210/endocr/bqz046

59. Shortall K., Djeghader A., Magner E., Soulimane T. Insights into aldehyde dehydrogenase enzymes: a structural perspective. Front. Mol. Biosci. 2021;8:659550. doi 10.3389/fmolb.2021.659550

60. Sohrabi S., Mor D.E., Kaletsky R., Keyes W., Murphy C.T. Highthroughput behavioral screen in C. elegans reveals Parkinson’s disease drug candidates. Commun. Biol. 2021;4(1):203. doi 10.1038/s42003-021-01731-z

61. Song M., Schnettler E., Venkatachalam A., Wang Y., Feldman L., Argenta P., Rodriguez-Rodriguez L., Ramakrishnan S. Increased expression of collagen prolyl hydroxylases in ovarian cancer is associated with cancer growth and metastasis. Am. J. Cancer Res. 2023;13(12):6051-6062

62. Thanvi B., Lo N., Robinson T. Vascular parkinsonism – an important cause of parkinsonism in older people. Age Ageing. 2005;34(2): 114-119. doi 10.1093/ageing/afi025

63. Tomkins J.E., Manzoni C. Advances in protein-protein interaction network analysis for Parkinson’s disease. Neurobiol. Dis. 2021;155: 105395. doi 10.1016/j.nbd.2021.105395

64. Trabjerg M.S., Andersen D.C., Huntjens P., Mørk K., Warming N., Kullab U.B., Skjønnemand M.-L.N., Oklinski M.K., Oklinski K.E., Bolther L., Kroese L.J., Pritchard C.E.J., Huijbers I.J., Corthals A., Søndergaard M.T., Kjeldal H.B., Pedersen C.F.M., Nieland J.D.V. Inhibition of carnitine palmitoyl-transferase 1 is a potential target in a mouse model of Parkinson’s disease. NPJ Parkinsons Dis. 2023; 9(1):6. doi 10.1038/s41531-023-00450-y

65. Tukey R.H., Strassburg C.P. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu. Rev. Pharmacol. Toxicol. 2000;40(1):581-616. doi 10.1146/annurev.pharmtox.40.1.581

66. Urban D., Lorenz J., Meyborg H., Ghosh S., Kintscher U., Kaufmann J., Fleck E., Kappert K., Stawowy P. Proprotein convertase furin enhances survival and migration of vascular smooth muscle cells via processing of pro-nerve growth factor. J. Biochem. 2013;153(2): 197-207. doi 10.1093/jb/mvs137

67. Vale T.C., Barbosa M.T., Caramelli P., Cardoso F. Vascular Parkinsonism and cognitive impairment: literature review, Brazilian studies and case vignettes. Dement. Neuropsychol. 2012;6(3):137-144. doi 10.1590/S1980-57642012DN06030005

68. Valente E.M., Abou-Sleiman P.M., Caputo V., Muqit M.M.K., Harvey K., Gispert S., Ali Z., Del Turco D., Bentivoglio A.R., Healy D.G., Albanese A., Nussbaum R., González-Maldonado R., Deller T., Salvi S., Cortelli P., Gilks W.P., Latchman D.S., Harvey R.J., Dallapiccola B., Auburger G., Wood N.W. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science. 2004;304(5674):1158-1160. doi 10.1126/science.1096284

69. Virmani A., Pinto L., Bauermann O., Zerelli S., Diedenhofen A., Binienda Z.K., Ali S.F., Van Der Leij F.R. The carnitine palmitoyl transferase (CPT) system and possible relevance for neuropsychiatric and neurological conditions. Mol. Neurobiol. 2015;52(2): 826-836. doi 10.1007/s12035-015-9238-7

70. Vos M., Geens A., Böhm C., Deaulmerie L., Swerts J., Rossi M., Craessaerts K., Leites E.P., Seibler P., Rakovic A., Lohnau T., De Strooper B., Fendt S.-M., Morais V.A., Klein C., Verstreken P. Cardiolipin promotes electron transport between ubiquinone and complex I to rescue PINK1 deficiency. J. Cell Biol. 2017;216(3):695-708. doi 10.1083/jcb.201511044

71. Wang Mingyue, Xie Y., Qin D. Proteolytic cleavage of proBDNF to mBDNF in neuropsychiatric and neurodegenerative diseases. Brain Res. Bull. 2021;166:172-184. doi 10.1016/j.brainresbull.2020.11.005

72. Wang Muyun, Wang K., Liao X., Hu H., Chen L., Meng L., Gao W., Li Q. Carnitine palmitoyltransferase system: a new target for antiinflammatory and anticancer therapy? Front. Pharmacol. 2021;12: 760581. doi 10.3389/fphar.2021.760581

73. Wang Yu, Yu W., Li S., Guo D., He J., Wang Yugang. Acetyl-CoA carboxylases and diseases. Front. Oncol. 2022;12:836058. doi 10.3389/fonc.2022.836058

74. Wey M.C.-Y., Fernandez E., Martinez P.A., Sullivan P., Goldstein D.S., Strong R. Neurodegeneration and motor dysfunction in mice lacking cytosolic and mitochondrial aldehyde dehydrogenases: implications for Parkinson’s disease. PLoS One. 2012;7(2):e31522. doi 10.1371/journal.pone.0031522

75. Wichaiyo S., Koonyosying P., Morales N.P. Functional roles of furin in cardio-cerebrovascular diseases. ACS Pharmacol. Transl. Sci. 2024; 7(3):570-585. doi 10.1021/acsptsci.3c00325

76. Wishart D.S., Guo A., Oler E., Wang F., Anjum A., Peters H., Dizon R., Sayeeda Z., Tian S., Lee B.L., Berjanskii M., Mah R., Yamamoto M., Jovel J., Torres-Calzada C., Hiebert-Giesbrecht M., Lui V.W., Varshavi Dorna, Varshavi Dorsa, Allen D., Arndt D., Khetarpal N., Sivakumaran A., Harford K., Sanford S., Yee K., Cao X., Budinski Z., Liigand J., Zhang L., Zheng J., Mandal R., Karu N., Dambrova M., Schiöth H.B., Greiner R., Gautam V. HMDB 5.0: the human metabolome database for 2022. Nucleic Acids Res. 2022;50(D1): D622-D631. doi 10.1093/nar/gkab1062

77. Wuolikainen A., Jonsson P., Ahnlund M., Antti H., Marklund S.L., Moritz T., Forsgren L., Andersen P.M., Trupp M. Multi-platform mass spectrometry analysis of the CSF and plasma metabolomes of rigorously matched amyotrophic lateral sclerosis, Parkinson’s di sease and control subjects. Mol. BioSyst. 2016;12(4):1287-1298. doi 10.1039/C5MB00711A

78. Xu Y., Xia D., Huang K., Liang M. Hypoxia-induced P4HA1 overexpression promotes post-ischemic angiogenesis by enhancing endothelial glycolysis through downregulating FBP1. J. Transl. Med. 2024;22(1):74. doi 10.1186/s12967-024-04872-x

79. Yakala G.K., Cabrera-Fuentes H.A., Crespo-Avilan G.E., Rattanasopa C., Burlacu A., George B.L., Anand K., Mayan D.C., Corlianò M., Hernández-Reséndiz S., Wu Z., Schwerk A.M.K., Tan A.L.J., Trigueros-Motos L., Chèvre R., Chua T., Kleemann R., Liehn E.A., Hausenloy D.J., Ghosh S., Singaraja R.R. FURIN inhibition reduces vascular remodeling and atherosclerotic lesion progression in mice. Arterioscler. Thromb. Vasc. Biol. 2019;39(3):387-401. doi 10.1161/ATVBAHA.118.311903

80. Yamada M., Hayashi H., Yuuki M., Matsushima N., Yuan B., Takagi N. Furin inhibitor protects against neuronal cell death induced by activated NMDA receptors. Sci. Rep. 2018;8(1):5212. doi 10.1038/s41598-018-23567-0

81. Yao V., Kaletsky R., Keyes W., Mor D.E., Wong A.K., Sohrabi S., Murphy C.T., Troyanskaya O.G. An integrative tissue-network approach to identify and test human disease genes. Nat. Biotechnol. 2018;36(11):1091-1099. doi 10.1038/nbt.4246

82. Zhao H., Wang C., Zhao N., Li W., Yang Z., Liu X., Le W., Zhang X. Potential biomarkers of Parkinson’s disease revealed by plasma metabolic profiling. J. Chromatogr. B. 2018;1081-1082:101-108. doi 10.1016/j.jchromb.2018.01.025

83. Zijlmans J.C.M., Thijssen H.O.M., Vogels O.J.M., Kremer H.P.H.M.P., Poels P.J.E., Schoonderwaldt H.C., Merx J.L., van’t Hof M.A., Thien Th., Horstink M.W.I.M. MRI in patients with suspected vascular parkinsonism. Neurology. 1995;45(12):2183-2188. doi 10.1212/WNL.45.12.2183

84. Zolotareva O., Saik O.V., Königs C., Bragina E.Yu., Goncharova I.A., Freidin M.B., Dosenko V.E., Ivanisenko V.A., Hofestädt R. Comorbidity of asthma and hypertension may be mediated by shared genetic dysregulation and drug side effects. Sci. Rep. 2019;9(1): 16302. doi 10.1038/s41598-019-52762-w