Annals of Clinical and Experimental NeurologyAnnals of Clinical and Experimental NeurologyАнналы клинической и экспериментальной неврологии2075-54732409-2533Eco-Vector138610.17816/ACEN.1386RHVBWUReviewsОбзорыReview ArticleMetabolic manifestations of Parkinson’s disease in cell models derived from induced pluripotent stem cellsМетаболические проявления болезни Паркинсона в клеточных моделях, полученных из индуцированных плюрипотентных стволовых клетокhttps://orcid.org/0000-0002-7853-6222KolotyevaNataliya A.КолотьеваНаталия Александровна
Russian Federation

Dr. Sci. (Med.), Associate Professor, Head, Laboratory of experimental and translational neurochemistry, Brain Institute

д-р мед. наук, доцент, зав. лаб. экспериментальной и трансляционной нейрохимии Института мозга

kolotyeva.n.a@neurology.ruhttps://orcid.org/0009-0008-8522-309XMudarisovaRegina S.МударисоваРегина Салаватовна
Russian Federation

postgraduate student, laboratory assistant, Laboratory of experimental and translational neurochemistry, Brain Institute

аспирант, лаборант-исследователь лаб. экспериментальной и трансляционной нейрохимии Института мозга

mudarisova.regina@bk.ruhttps://orcid.org/0000-0001-9619-4679RozanovaNatalia A.РозановаНаталья Александровна
Russian Federation

postgraduate student, researcher, Laboratory of experimental and translational neurochemistry, Brain Institute

аспирант, н. с. лаб. нейробиологии и тканевой инженерии Института мозга

nataliarozanovaa@gmail.comhttps://orcid.org/0009-0007-4195-2533BerdnikovArseniy K.БердниковАрсений Константинович
Russian Federation

postgraduate student, laboratory assistant, Laboratory of experimental and translational neurochemistry, Brain Institute

аспирант, лаборант-исследователь лаб. нейробиологии и тканевой инженерии Института мозга

akberdnikov@gmail.comhttps://orcid.org/0009-0008-3905-1928NovikovaSvetlana V.НовиковаСветлана Викторовна
Russian Federation

graduate student, Laboratory of experimental and translational neurochemistry, Brain Institute

аспирант, н. с. лаб. нейробиологии и тканевой инженерии Института мозга

levik_82@mail.ruhttps://orcid.org/0000-0001-5742-8356KomlevaYulia K.КомлеваЮлия Константиновна
Russian Federation

Dr. Sci. (Med.), Associate Professor, senior researcher, Laboratory of experimental and translational neurochemistry, Brain Institute

д-р мед. наук, доцент, с. н. с. лаб. нейробиологии и тканевой инженерии Института мозга

yuliakomleva@mail.ruRussian Center of Neurology and NeurosciencesРоссийский центр неврологии и нейронаук1010202519363720606202513082025Copyright ©; 2025, Kolotyeva N.A., Mudarisova R.S., Rozanova N.A., Berdnikov A.K., Novikova S.V., Komleva Y.K.Copyright ©; 2025, Колотьева Н.А., Мударисова Р.С., Розанова Н.А., Бердников А.К., Новикова С.В., Комлева Ю.К.2025Kolotyeva N.A., Mudarisova R.S., Rozanova N.A., Berdnikov A.K., Novikova S.V., Komleva Y.K.Колотьева Н.А., Мударисова Р.С., Розанова Н.А., Бердников А.К., Новикова С.В., Комлева Ю.К.https://creativecommons.org/licenses/by/4.0https://annaly-nevrologii.com/pathID/article/view/1386

Induced pluripotent stem cell (iPSC)-based models represent an innovative approach to studying the pathogenesis of inherited Parkinson’s disease (PD) at molecular and cellular levels. The ability to derive neurons, astrocytes, and microglia carrying SNCA gene mutations from iPSCs significantly advances our understanding of key metabolic disturbances in PD. Each specific type of SNCA gene mutation (A53T, A30P, triplications, duplications, etc.) exhibits individual effects on functional and biochemical characteristics of differentiated cells. These differences involve synaptogenesis, extramitochondrial oxygen consumption, and protein metabolism. The diversity of effects makes critical the selection of strictly defined iPSC lines depending on research objectives. The aim of this review is to examine metabolic features of brain cells derived from iPSCs with inherited PD associated with SNCA mutations, as well as the potential of using iPSCs to develop personalized in vitro models for understanding disease mechanisms. This approach will facilitate identification of new therapeutic targets and refinement of existing technologies for diagnosis and targeted therapy.

Модели на основе индуцированных плюрипотентных стволовых клеток (ИПСК) являются частью инновационного подхода к изучению патогенеза наследственных форм болезни Паркинсона на молекулярном и клеточном уровнях. Возможность получения из ИПСК нейронов, астроцитов и микроглии, несущих мутации в гене SNCA, позволяет существенно продвинуть понимание ключевых метаболических нарушений, сопровождающих данную патологию. Каждый отдельный тип мутаций в гене SNCA (A53T, A30P, трипликации, дупликации и др.) по-разному влияет на функциональные и биохимические характеристики дифференцированных клеток. Эти различия затрагивают процессы синаптогенеза, внемитохондриального потребления кислорода и белкового обмена. Разнообразие эффектов делает актуальным выбор строго определённых линий ИПСК в зависимости от задач исследования. Целью обзора является изучение метаболических особенностей клеток головного мозга, полученных из ИПСК с генетической формой болезни Паркинсона, ассоциированной с мутациями в гене SNCA, а также потенциала использования ИПСК для разработки персонализированных моделей in vitro для понимания механизмов заболевания, что будет способствовать выявлению новых мишеней и усовершенствованию существующих технологий для диагностики и таргетной терапии.

Parkinson’s diseaseSNCA genemetabolic plasticityinduced pluripotent stem cellsastrocytesneuronsmicrogliaболезнь Паркинсонаген SNCAметаболическая пластичностьиндуцированные плюрипотентные стволовые клеткиастроцитынейронымикроглияRussian Science FoundationРоссийский научный фонд24-25-00239Müller-Nedebock AC, Dekker MCJ, Farrer MJ, et al. Different pieces of the same puzzle: a multifaceted perspective on the complex biological basis of Parkinson’s disease. NPJ Parkinsons Dis. 2023;9(1):110. doi: 10.1038/s41531-023-00535-8Cherian A, Divya KP. Genetics of Parkinson’s disease. Acta Neurol Belg. 2020;120(6):1297–1305. doi: 10.1007/s13760-020-01473-5Zanon A, Pramstaller PP, Hicks AA, Pichler I. Environmental and genetic variables influencing mitochondrial health and Parkinson’s disease penetrance. Parkinsons Dis. 2018;2018:8684906. doi: 10.1155/2018/8684906Ferrari E, Cardinale A, Picconi B, Gardoni F. From cell lines to pluripotent stem cells for modelling Parkinson’s Disease. J Neurosci Methods. 2020;340:108741. doi: 10.1016/j.jneumeth.2020.108741Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917– 1920. doi: 10.1126/science.1151526Huang Y, Tan S. Direct lineage conversion of astrocytes to induced neural stem cells or neurons. Neurosci Bull. 2015;31(3):357–367. doi: 10.1007/s12264-014-1517-1Pankratz N, Foroud T. Genetics of Parkinson disease. Genet Med. 2007;9(12):801–811. doi: 10.1097/gim.0b013e31815bf97cHenrich MT, Oertel WH, Surmeier DJ, Geibl FF. Mitochondrial dysfunction in Parkinson’s disease — a key disease hallmark with therapeutic potential. Mol Neurodegener. 2023;18(1):83. doi: 10.1186/s13024-023-00676-7Белова О.В., Арефьева Т.И., Москвина С.Н. Иммуновоспалительные аспекты болезни Паркинсона. Журнал неврологии и психиатрии им. С.С. Корсакова. 2020;120(2):110–119Kuo G, Kumbhar R, Blair W, et al. Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions. Mol Neurodegener. 2025;20(1):10. doi: 10.1186/s13024-025-00797-1Pozdyshev DV, Leisi EV, Muronetz VI, et al. Cytotoxicity of α-synuclein amyloid fibrils generated with phage chaperonin OBP. Biochem Biophys Res Commun. 2025;742:151127. doi: 10.1016/j.bbrc.2024.151127Zohoorian-Abootorabi T, Meratan AA, Jafarkhani S, et al. Modulation of cytotoxic amyloid fibrillation and mitochondrial damage of α-synuclein by catechols mediated conformational changes. Sci Rep. 2023;13(1):5275. doi: 10.1038/s41598-023-32075-9Muronetz VI, Kudryavtseva SS, Leisi EV, et al. Regulation by different types of chaperones of amyloid transformation of proteins involved in the development of neurodegenerative diseases. Int J Mol Sci. 2022;23(5):2747. doi: 10.3390/ijms23052747Salmina AB. Metabolic plasticity in developing and aging brain. Neurochemical Journal. 2023;17(3):325–337. doi: 10.1134/S1819712423030157Salmina AB, Gorina YV, Komleva YK, et al. Early life stress and metabolic plasticity of brain cells: impact on neurogenesis and angiogenesis. Biomedicines. 2021;9(9):1092. doi: 10.3390/biomedicines9091092Takahashi S. Metabolic compartmentalization between astroglia and neurons in physiological and pathophysiological conditions of the neurovascular unit. Neuropathology. 2020;40(2):121–137. doi: 10.1111/neup.12639Van Steenbergen V, Lavoie-Cardinal F, Kazwiny Y, et al. Nano-positioning and tubulin conformation contribute to axonal transport regulation of mitochondria along microtubules. Proc Natl Acad Sci U S A. 2022;119(45):e2203499119. doi: 10.1073/pnas.2203499119Karagiannis A, Gallopin T, Lacroix A, et al. Lactate is an energy substrate for rodent cortical neurons and enhances their firing activity. Elife. 2021;10:e71424. doi: 10.7554/eLife.71424Selivanov VA, Zagubnaya OA, Nartsissov YR, Cascante M. Unveiling a key role of oxaloacetate-glutamate interaction in regulation of respiration and ROS generation in nonsynaptic brain mitochondria using a kinetic model. PLoS One. 2021;16(8):e0255164. doi: 10.1371/journal.pone.0255164Morant-Ferrando B, Jimenez-Blasco D, Alonso-Batan P, et al. Fatty acid oxidation organizes mitochondrial supercomplexes to sustain astrocytic ROS and cognition. Nat Metab. 2023;5(8):1290–1302. doi: 10.1038/s42255-023-00835-6Komatsuzaki S, Ediga RD, Okun JG, et al. Impairment of astrocytic glutaminolysis in glutaric aciduria type I. J Inherit Metab Dis. 2018;41(1):91–99. doi: 10.1007/s10545-017-0096-5de Tredern E, Rabah Y, Pasquer L, et al. Glial glucose fuels the neuronal pentose phosphate pathway for long-term memory. Cell Rep. 2021;36(8):109620. doi: 10.1016/j.celrep.2021.109620Mishra A, Gordon GR, MacVicar BA, Newman EA. Astrocyte regulation of cerebral blood flow in health and disease. Cold Spring Harb Perspect Biol. 2024;16(4):a041354. doi: 10.1101/cshperspect.a041354Salmina AB, Kuvacheva NV, Morgun AV, et al. Glycolysis-mediated control of blood-brain barrier development and function. Int J Biochem Cell Biol. 2015;64:174–184. doi: 10.1016/j.biocel.2015.04.005Veys K, Fan Z, Ghobrial M, et al. Role of the GLUT1 glucose transporter in postnatal CNS angiogenesis and blood-brain barrier integrity. Circ Res. 2020;127(4):466–482. doi: 10.1161/CIRCRESAHA.119.316463Cheng J, Zhang R, Xu Z, et al. Early glycolytic reprogramming controls microglial inflammatory activation. J Neuroinflammation. 2021;18(1):129. doi: 10.1186/s12974-021-02187-yBielanin JP, Sun D. Significance of microglial energy metabolism in maintaining brain homeostasis. Transl Stroke Res. 2023;14(4):435–437. doi: 10.1007/s12975-022-01069-6Bernier LP, York EM, Kamyabi A, et al. Microglial metabolic flexibility supports immune surveillance of the brain parenchyma. Nat Commun. 2020;11(1):1559. doi: 10.1038/s41467-020-15267-zBenarroch E. What are the roles of pericytes in the neurovascular unit and its disorders? Neurology. 2023;100(20):970–977. doi: 10.1212/WNL.000000000020737Liu LR, Liu JC, Bao JS, et al. Interaction of microglia and astrocytes in the neurovascular unit. Front Immunol. 2020;11:1024. doi: 10.3389/fimmu.2020.01024Ioghen O, Chițoiu L, Gherghiceanu M, et al. CD36 — a novel molecular target in the neurovascular unit. Eur J Neurosci. 2021;53(8):2500–2510. doi: 10.1111/ejn.15147Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276(5321):2045–2047. doi: 10.1126/science.276.5321.2045Deas E, Cremades N, Angelova PR, et al. Alpha-Synuclein oligomers interact with metal ions to induce oxidative stress and neuronal death in Parkinson’s disease. Antioxid Redox Signal. 2016;24(7):376–391. doi: 10.1089/ars.2015.6343Zarranz JJ, Alegre J, Gómez-Esteban JC, et al.The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol. 2004;55(2):164–173. doi: 10.1002/ana.10795.Lesage S, Anheim M, Letournel F, et al. G51D α-synuclein mutation causes a novel parkinsonian-pyramidal syndrome. Ann Neurol. 2013;73(4):459–471. doi: 10.1002/ana.23894Pasanen P, Myllykangas L, Siitonen M, et al. Novel α-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson’s disease-type pathology. Neurobiol Aging. 2014;35(9):2180.e1-5. doi: 10.1016/j.neurobiolaging.2014.03.024Ibáñez P, Bonnet AM, Débarges B, et al. Causal relation between alpha-synuclein gene duplication and familial Parkinson’s disease. Lancet. 2004;364(9440):1169–1171. doi: 10.1016/S0140-6736(04)17104-3Mouroux V, Douay X, Lincoln S, et al. Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet. 2004;364(9440):1167– 1169. doi: 10.1016/S0140-6736(04)17103-1Singleton AB, Farrer M, Johnson J, et al. Alpha-synuclein locus triplication causes Parkinson’s disease. Science. 2003;302(5646):841. doi: 10.1126/science.1090278Ferese R, Modugno N, Campopiano R, et al. Four copies of SNCA responsible for autosomal dominant Parkinson’s disease in two Italian siblings. Parkinsons Dis. 2015;2015:546462. doi: 10.1155/2015/546462Devine MJ, Ryten M, Vodicka P, et al. Parkinson’s disease induced pluripotent stem cells with triplication of the α-synuclein locus. Nat Commun. 2011;2:440. doi: 10.1038/ncomms1453Suzuki H, Egawa N, Imamura K, et al. Mutant α-synuclein causes death of human cortical neurons via ERK1/2 and JNK activation. Mol Brain. 2024;17(1):14. doi: 10.1186/s13041-024-01086-6Fernandes HJR, Patikas N, Foskolou S, et al. Single-cell transcriptomics of Parkinson’s disease human in vitro models reveals dopamine neuron-specific stress responses. Cell Rep. 2020;33(2):108263. doi: 10.1016/j.celrep.2020Vetchinova AS, Kapkaeva MR, Ivanov MV, et al. Mitochondrial dysfunction in dopaminergic neurons derived from patients with LRRK2- and SNCA-associated genetic forms of Parkinson’s disease. Curr Issues Mol Biol. 2023;45(10):8395–8411. doi: 10.3390/cimb45100529Krzisch M, Yuan B, Chen W, et al. The A53T mutation in α-synuclein enhances proinflammatory activation in human microglia upon inflammatory stimulus. Biol Psychiatry. 2025;97(7):730–742. doi: 10.1016/j.biopsych.2024.07.011Oliveira LM, Falomir-Lockhart LJ, Botelho MG, et al. Elevated α-synuclein caused by SNCA gene triplication impairs neuronal differentiation and maturation in Parkinson’s patient-derived induced pluripotent stem cells. Cell Death Dis. 2015;6(11):e1994. doi: 10.1038/cddis.2015.318Kouroupi G, Taoufik E, Vlachos IS, et al. Defective synaptic connectivity and axonal neuropathology in a human iPSC-based model of familial Parkinson’s disease. Proc Natl Acad Sci U S A. 2017;114(18):E3679– E3688. doi: 10.1073/pnas.1617259114Nordengen K, Morland C. From Synaptic physiology to synaptic pathology: the enigma of α-Synuclein. Int J Mol Sci. 2024;25(2):986. doi: 10.3390/ijms25020986Zambon F, Cherubini M, Fernandes HJR, et al. Cellular α-synuclein pathology is associated with bioenergetic dysfunction in Parkinson’s iPSC-derived dopamine neurons. Hum Mol Genet. 2019;28(12):2001– 2013. doi: 10.1093/hmg/ddz038Diao X, Wang F, Becerra-Calixto A, et al. Induced pluripotent stem cell-derived dopaminergic neurons from familial Parkinson’s disease patients display α-synuclein pathology and abnormal mitochondrial morphology. Cells. 2021;10(9):2402. doi: 10.3390/cells10092402Iannielli A, Luoni M, Giannelli SG, et al. Modeling native and seeded Synuclein aggregation and related cellular dysfunctions in dopaminergic neurons derived by a new set of isogenic iPSC lines with SNCA multiplications. Cell Death Dis. 2022;13(10):881. doi: 10.1038/s41419-022-05330-6Barbuti PA, Antony PMA, Novak G, et al. IPSC-derived midbrain astrocytes from Parkinson’s disease patients carrying pathogenic SNCA mutations exhibit alpha-synuclein aggregation, mitochondrial fragmentation and excess calcium release: preprint. 2020. doi: 10.1101/2020.04.27.053470Heman-Ackah SM, Manzano R, Hoozemans JJM, et al. Alpha-synuclein induces the unfolded protein response in Parkinson’s disease SNCA triplication iPSC-derived neurons. Hum Mol Genet. 2017;26(22):4441– 4450. doi: 10.1093/hmg/ddx331Chung CY, Khurana V, Auluck PK, et al. Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons. Science. 2013;342(6161):983–987. doi: 10.1126/science.1245296Stojkovska I, Wani WY, Zunke F, et al. Rescue of α-synuclein aggregation in Parkinson’s patient neurons by synergistic enhancement of ER proteostasis and protein trafficking. Neuron. 2022;110(3):436–451.e11. doi: 10.1016/j.neuron.2021.10.032Zigoneanu IG, Yang YJ, Krois AS, et al. Interaction of α-synuclein with vesicles that mimic mitochondrial membranes. Biochim Biophys Acta. 2012;1818(3):512–519. doi: 10.1016/j.bbamem.2011.11.024Diao J, Burré J, Vivona S, et al. Native α-synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and synaptobrevin-2/VAMP2. Elife. 2013;2:e00592. doi: 10.7554/eLife.00592Li W, Lesuisse C, Xu Y, et al. Stabilization of alpha-synuclein protein with aging and familial parkinson’s disease-linked A53T mutation. J Neurosci. 2004;24(33):7400–7409. doi: 10.1523/JNEUROSCI.1370-04.2004Ohgita T, Namba N, Kono H, et al. Mechanisms of enhanced aggregation and fibril formation of Parkinson’s disease-related variants of α-synuclein. Sci Rep. 2022;12(1):6770. doi: 10.1038/s41598-022-10789-6Tang Q, Gao P, Arzberger T, et al. Alpha-synuclein defects autophagy by impairing SNAP29-mediated autophagosome-lysosome fusion. Cell Death Dis. 2021;12(10):854. doi: 10.1038/s41419-021-04138-0Ludtmann MHR, Angelova PR, Horrocks MH, et al. α-Synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson’s disease. Nat Commun. 2018;9(1):2293. doi: 10.1038/s41467-018-04422-2Byers B, Cord B, Nguyen HN, et al. SNCA triplication Parkinson’s patient’s iPSC-derived DA neurons accumulate α-synuclein and are susceptible to oxidative stress. PLoS One. 2011;6(11):e26159. doi: 10.1371/journal.pone.0026159Little D, Luft C, Mosaku O, et al. A single cell high content assay detects mitochondrial dysfunction in iPSC-derived neurons with mutations in SNCA. Sci Rep. 2018;8(1):9033. doi: 10.1038/s41598-018-27058-0Dettmer U, Newman AJ, Soldner F, et al. Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nat Commun. 2015;6:7314. doi: 10.1038/ncomms8314Khurana V, Peng J, Chung CY, et al. Genome-scale networks link neuro- degenerative disease genes to α-synuclein through specific molecular pathways. Cell Syst. 2017;4(2):157–170.e14. doi: 10.1016/j.cels.2016.12.011