{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:00:37Z","timestamp":1791846037927,"version":"4.3.4"},"reference-count":134,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T00:00:00Z","timestamp":1729209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is a progressive age-related neurodegenerative disorder affecting millions of people worldwide. Essentially, it is characterised by selective degeneration of dopamine neurons of the nigro-striatal pathway and intraneuronal aggregation of misfolded \u03b1-synuclein with formation of Lewy bodies and Lewy neurites. Moreover, specific small molecules of intermediary metabolism may have a definite pathophysiological role in PD. These include dopamine, levodopa, reduced glutathione, glutathione disulfide\/oxidised glutathione, and the micronutrients thiamine and \u00df-Hydroxybutyrate. Recent research indicates that these small molecules can interact with \u03b1-synuclein and regulate its folding and potential aggregation. In this review, we discuss the current knowledge on interactions between \u03b1-synuclein and both the small molecules of intermediary metabolism in the brain relevant to PD, and many other natural and synthetic small molecules that regulate \u03b1-synuclein aggregation. Additionally, we analyse some of the relevant molecular mechanisms potentially involved. A better understanding of these interactions may have relevance for the development of rational future therapies. In particular, our observations suggest that the micronutrients \u00df-Hydroxybutyrate and thiamine might have a synergistic therapeutic role in halting or reversing the progression of PD and other neuronal \u03b1-synuclein disorders.<\/jats:p>","DOI":"10.3390\/ijms252011198","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T05:03:49Z","timestamp":1729227829000},"page":"11198","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Small Molecules, \u03b1-Synuclein Pathology, and the Search for Effective Treatments in Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9515-0014","authenticated-orcid":false,"given":"Gian Pietro","family":"Sechi","sequence":"first","affiliation":[{"name":"Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Margherita","family":"Sechi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1146\/annurev-neuro-100720-034518","article-title":"Parkinson\u2019s disease genetics and pathophysiology","volume":"44","author":"Zoghbi","year":"2021","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/S0140-6736(23)01478-2","article-title":"The pathogenesis of Parkinson\u2019s disease","volume":"403","author":"Morris","year":"2024","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0891-0618(01)00100-4","article-title":"Chemical neuroanatomy of the basal ganglia\u2014Normal and in Parkinson\u2019s disease","volume":"22","author":"Hornykiewicz","year":"2001","journal-title":"J. Chem. Neuroanat."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1007\/BF01485901","article-title":"Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system","volume":"38","author":"Ehringer","year":"1960","journal-title":"Klin. Wochenschr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/0304-3940(82)90390-1","article-title":"Parkinson\u2019s disease: A disorder due to a nigral glutathione deficiency","volume":"33","author":"Perry","year":"1982","journal-title":"Neurosci. Lett."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1002\/ana.410360305","article-title":"Alterations in glutathione levels in Parkinson\u2019s disease and other neurodegenerative disorders affecting basal ganglia","volume":"36","author":"Sian","year":"1994","journal-title":"Ann. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1016\/0140-6736(91)92989-F","article-title":"Parkinson\u2019s disease. Pathophysiology","volume":"337","author":"Agid","year":"1991","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1212\/WNL.42.9.1702","article-title":"Kynurenine pathway abnormalities in Parkinson\u2019s disease","volume":"42","author":"Ogawa","year":"1992","journal-title":"Neurology"},{"key":"ref_9","first-page":"549","article-title":"Metabolite and peptide levels in plasma and CSF differentiating healthy controls from patients with newly diagnosed Parkinson\u2019s disease","volume":"4","author":"Trupp","year":"2014","journal-title":"J. Park. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1021\/cn400149k","article-title":"Ceftriaxone blocks the polymerization of \u03b1-synuclein and exerts neuroprotective effects in vitro","volume":"5","author":"Ruzza","year":"2014","journal-title":"ACS Chem. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Rodger, A.T., Alnasser, M., and Carter, W.G. (2023). Are therapies that target \u03b1-synuclein effective at halting Parkinson\u2019s disease progression? A systematic review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241311022"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Brembati, V., Faustini, G., Longhena, F., and Bellucci, A. (2023). Alpha synuclein post translational modifications: Potential targets for Parkinson\u2019s disease therapy?. Front. Mol. Neurosci., 16.","DOI":"10.3389\/fnmol.2023.1197853"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/S1474-4422(23)00405-2","article-title":"A biological definition of neuronal \u03b1-synuclein disease: Towards an integrated staging system for research","volume":"23","author":"Simuni","year":"2024","journal-title":"Lancet Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/s41582-019-0155-7","article-title":"Emerging therapies in Parkinson disease-repurposed drugs and new approaches","volume":"15","author":"Elkouzi","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Mohammed, S., Russo, I., and Ramazzina, I. (2023). Uncovering the role of natural and synthetic small molecules uncounteracting the burden of \u03b1-Synuclein aggregates and related toxicity in different models of Parkinson\u2019s disease. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241713370"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Mitchell, C.L., and Kurouski, D. (2024). Novel strategies in Parkinson\u2019s disease treatment: A review. Front. Mol. Neurosci., 17.","DOI":"10.3389\/fnmol.2024.1431079"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Erro, R., Vitale, C., Amboni, M., Picillo, M., Longo, K., Santangelo, G., De Rosa, A., Allocca, R., Giordano, F., and Orefice, G. (2013). The heterogeneity of early Parkinson\u2019s disease: A cluster analysis on newly diagnosed untreated patients. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070244"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/nan.12298","article-title":"Review: Sporadic Parkinson\u2019s disease: Development and distribution of \u03b1-synuclein pathology","volume":"42","author":"Braak","year":"2016","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"158101","DOI":"10.1103\/PhysRevLett.121.158101","article-title":"Multiphysics of prionlike diseases: Progression and atrophy","volume":"12","author":"Weickenmeier","year":"2018","journal-title":"Phys. Rev. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Saramowicz, K., Siwecka, N., Galita, G., Kucharska-Lusina, A., Rozpedek-Kaminska, W., and Majsterek, I. (2024). Alpha-Synuclein contribution to neuronal and glia damage in Parkinson\u2019s disease. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010360"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.tins.2013.06.007","article-title":"Molecular nexopathies: A new paradigm of neurodegenerative disease","volume":"36","author":"Warren","year":"2013","journal-title":"Trends Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2643","DOI":"10.1038\/s41467-020-16386-3","article-title":"Parkinson\u2019s disease associated mutation E46K of \u03b1-synuclein triggers the formation of a distinct fibril structure","volume":"11","author":"Zhao","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/978-3-319-49969-7_11","article-title":"Interaction of LRRK2 and \u03b1-synuclein in Parkinson\u2019s disease","volume":"14","author":"Daher","year":"2017","journal-title":"Adv. Neurobiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1007\/s00401-019-01995-0","article-title":"LRRK2 modifies \u03b1-syn pathology and spread in mouse models and humans neurons","volume":"137","author":"Bieri","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s40035-019-0181-9","article-title":"Effect of the micro-environment on \u03b1-synuclein conversion and implication in seeded conversion assays","volume":"9","author":"Candelise","year":"2020","journal-title":"Transl. Neurodegener."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Atarod, D., Mamashli, F., Ghasemi, A., Moosavi-Movahdi, F., Pirhaghi, M., Nedaei, H., Muronetz, V., Haertl\u00e9, T., Tatzelt, J., and Riazi, G. (2022). Bivalent metal ions induce formation of \u03b1-synuclein fibril polymorphs with different cytotoxicities. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-15472-4"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1602\/neurorx.2.1.3","article-title":"The blood-brain barrier: Bottleneck in brain drug development","volume":"2","author":"Pardrige","year":"2005","journal-title":"NeuroRx"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4383","DOI":"10.1021\/acschemneuro.3c00717","article-title":"Glutathione depletion and concomitant elevation of susceptibility in patients with Parkibson\u2019s disease: State-of-the-art MR Spectroscopy and neuropsychological study","volume":"14","author":"Shukla","year":"2023","journal-title":"ACS Chem. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.1172\/JCI114666","article-title":"Evidence for carrier-mediated transport of glutathione across the blood-brain barrier in the rat","volume":"85","author":"Kannan","year":"1990","journal-title":"J. Clin. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1016\/S0278-5846(96)00103-0","article-title":"Reduced intravenous glutathione in the treatment of early Parkinson\u2019s disease","volume":"20","author":"Sechi","year":"1996","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1002\/mds.22401","article-title":"Randomized, double-blind, pilot evaluation of intravenous glutathione in Parkinson\u2019s disease","volume":"24","author":"Hauser","year":"2009","journal-title":"Mov. Disord."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/0304-3940(93)90271-L","article-title":"The effects of thiamin and its phosphate esters on dopamine release in the rat striatum","volume":"158","author":"Yamashita","year":"1993","journal-title":"Neurosci. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/0376-8716(88)90017-8","article-title":"The influence of thiamine deficiency and ethanol on rat brain catecholamines","volume":"22","author":"Sjoquist","year":"1988","journal-title":"Drug Alcohol Depend."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S0304-3940(99)00515-7","article-title":"Cerebrospinal fluid levels of thiamine in patients with Parkinson\u2019s disease","volume":"271","author":"Molina","year":"1999","journal-title":"Neurosci. Lett."},{"key":"ref_35","first-page":"211","article-title":"The beneficial role of thiamine in Parkinson\u2019s disease: Preliminary report","volume":"2","author":"Luong","year":"2012","journal-title":"J. Neurol. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1172\/JCI200318797","article-title":"D-\u00df-Hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson\u2019s disease","volume":"112","author":"Tieu","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1212\/01.WNL.0000152046.11390.45","article-title":"Treatment of Parkinson disease with diet-induced hyperketonemia: A feasibility study","volume":"64","author":"Vanitallie","year":"2005","journal-title":"Neurology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/42166","article-title":"Alpha-synuclein in Lewy bodies","volume":"388","author":"Spillantini","year":"1997","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1111\/jnc.12226","article-title":"Oxidative and nitrative alpha-synuclein modifications and proteostatic stress: Implications for disease mechanisms and interventions in synucleinopathies","volume":"125","author":"Schildknecht","year":"2013","journal-title":"J. Neurochem."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Caggiu, E., Arru, G., Hosseini, S., Niegowska, M., Sechi, G., Zarbo, I.R., and Sechi, L.A. (2019). Inflammation, infectious triggers, and Parkinson\u2019s disease. Front. Neurol., 10.","DOI":"10.3389\/fneur.2019.00122"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1007\/s12035-012-8369-3","article-title":"The central theme of Parkinson\u2019s disease: \u03b1-synuclein","volume":"47","author":"Ozansoy","year":"2012","journal-title":"Mol. Neurobiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.ijbiomac.2016.10.021","article-title":"A-Synuclein aggregation and its modulation","volume":"100","author":"Ghosh","year":"2017","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.tins.2024.01.002","article-title":"Protein-protein interactions regulating \u03b1-synuclein pathology","volume":"47","author":"Wang","year":"2024","journal-title":"Trends Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1096\/fj.03-0770fje","article-title":"Dopamine and L-dopa disaggregate amyloid fibrils: Implications for Parkinson\u2019s and Alzheimer\u2019s disease","volume":"18","author":"Li","year":"2004","journal-title":"FASEB J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s13024-019-0332-6","article-title":"Impaired dopamine metabolism in Parkinson\u2019s disease pathogenesis","volume":"14","author":"Masato","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1038\/nn.4641","article-title":"Dopamine induces soluble alpha-synuclein oligomers and nigrostriatal degeneration","volume":"20","author":"Mor","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/mds.27607","article-title":"The usual suspects, dopamine and alpha-synuclein, conspire to cause neurodegeneration","volume":"34","author":"Mor","year":"2019","journal-title":"Mov. Disord."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0014-5793(03)00081-4","article-title":"Oxidized glutathione stimulated the amyloid formation of alpha-synuclein","volume":"537","author":"Paik","year":"2003","journal-title":"FEBS Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1152\/ajplegacy.1976.230.3.619","article-title":"Beta-hydroxybutyrate transport in rat brain: Developmental and dietary modulations","volume":"230","author":"Moore","year":"1976","journal-title":"Am. J. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/S1474-4422(07)70104-7","article-title":"Wernicke\u2019s encephalopathy: New clinical settings and recent advances in diagnosis and management","volume":"6","author":"Sechi","year":"2007","journal-title":"Lancet Neurol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1021\/acschemneuro.3c00029","article-title":"New therapeutic paradigms in neonatal hypoxic-ischemic encephalopathy","volume":"14","author":"Sechi","year":"2023","journal-title":"ACS Chem. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Sechi, G., Bardanzellu, F., Pintus, M.C., Sechi, M.M., Marcialis, M.A., and Fanos, V. (2022). Thiamine as a possible neuroprotective strategy in neonatal hypoxic-ischemic encephalopathy. Antioxidants, 11.","DOI":"10.3390\/antiox11010042"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jns.2012.02.008","article-title":"Thiamine and Parkinson\u2019s disease","volume":"316","author":"Nguyen","year":"2012","journal-title":"J. Neurol. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Norwitz, N.G., Hu, M.T., and Clarke, K. (2019). The mechanisms by which the ketone body D-\u00df- Hydroxybutyrate may improve the multiple cellular pathologies of Parkinson\u2019s disease. Front. Nutr., 6.","DOI":"10.3389\/fnut.2019.00063"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/s41565-024-01621-5","article-title":"A charge-dependent long-ranged force drives tailored assembly of matter in solution","volume":"19","author":"Wang","year":"2024","journal-title":"Nat. Nanotechnol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s13024-020-00368-6","article-title":"Initiation and propagation of \u03b1-synuclein aggregation in the nervous system","volume":"15","author":"Hijaz","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"621","DOI":"10.18632\/aging.100683","article-title":"D-beta-hydroxybutyrate extends lifespan in C. elegans","volume":"6","author":"Edwards","year":"2014","journal-title":"Aging"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1385\/JMN:28:2:179","article-title":"Alpha-synuclein fission yeast model: Concentration-dependent aggregation without plasma membrane localization and toxicity","volume":"28","author":"Brandis","year":"2006","journal-title":"J. Mol. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"665","DOI":"10.3177\/jnsv.44.665","article-title":"Thiamin-binding protein from sunflowers seeds","volume":"44","author":"Watanabe","year":"1998","journal-title":"J. Nutr. Sci. Vitaminol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1152\/physrev.00029.2006","article-title":"Nitric oxide and peroxynitrite in health and disease","volume":"87","author":"Pacher","year":"2007","journal-title":"Physiol. Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"6346","DOI":"10.1074\/jbc.275.9.6346","article-title":"Dityrosine formation outcompetes tyrosine nitration at low steady-state concentrations of peroxynitrite","volume":"275","author":"Pfeiffer","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2852","DOI":"10.1110\/ps.04947204","article-title":"Peroxidative aggregation of \u03b1-synuclein requires tyrosines","volume":"13","author":"Olteanu","year":"2004","journal-title":"Protein Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"13604","DOI":"10.1021\/bi801884z","article-title":"Alpha-synuclein conformation affects its tyrosine-dependent oxidative aggregation","volume":"47","author":"Ruf","year":"2008","journal-title":"Biochemistry"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Al-Hilaly, Y.K., Biasetti, L., Blakeman, B.J.F., Pollack, S.J., Zibaee, S., Abdul-Sada, A., Thorpe, J.R., Xue, W.-F., and Serpell, L.C. (2016). The involvement of dityrosine crosslinking in \u03b1-synuclein assembly and deposition in Lewy bodies in Parkinson\u2019s disease. Sci. Rep., 6.","DOI":"10.1038\/srep39171"},{"key":"ref_65","first-page":"1031","article-title":"Thiamine inhibits formation of dityrosine, a specific marker of oxidative injury, in reactions catalyzed by oxoferryl forms of hemoglobin","volume":"73","author":"Stepuro","year":"2008","journal-title":"Biochemistry"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1111\/j.1749-6632.1994.tb21791.x","article-title":"Peroxynitrite versus hydroxyl radical: The role of nitric oxide in superoxide-dependent cerebral injury","volume":"738","author":"Beckman","year":"1994","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Srinivasan, E., Chandrasekhar, G., Chandrasekhar, P., Anbarasu, K., Vickram, A.S., Karunakaran Rajasekaran, R., and Srikumar, P.S. (2021). Alpha-synuclein aggregation in Parkinson\u2019s disease. Front. Med., 8.","DOI":"10.3389\/fmed.2021.736978"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1186\/s40478-022-01468-8","article-title":"Prominent astrocytic alpha-synuclein pathology with unique post-translational modification signatures unveiled across Lewy body disorders","volume":"10","author":"Altay","year":"2022","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Fields, C.R., Bengoa-Vengnlory, N., and Wade-Martins, R. (2019). Targeting alpha-synuclein as a therapy for Parkinson\u2019s disease. Front. Mol. Neurosci., 12.","DOI":"10.3389\/fnmol.2019.00299"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.expneurol.2017.10.003","article-title":"Therapeutic approaches to target alpha-synuclein pathology","volume":"298","author":"Brundin","year":"2017","journal-title":"Exp. Neurol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1126\/science.aaf3934","article-title":"\u00df2-Adrenoreceptor is a regulator of the \u03b1-synuclein gene driving risk of Parkinson\u2019s disease","volume":"357","author":"Mittal","year":"2017","journal-title":"Science"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Liu, Y., Liu, H., and Tang, W.H. (2019). Exosomes: Biogenesis, biologic function and clinical potential. Cell Biosci., 9.","DOI":"10.1186\/s13578-019-0282-2"},{"key":"ref_73","first-page":"142372","article-title":"The anticholinesterase phenserine and its enantiomer posiphen as 5\u2019untranslated-region-directed translation blockers of the Parkinson\u2019s alpha synuclein expression","volume":"2012","author":"Mikkilineni","year":"2012","journal-title":"Parkinsons Dis."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"152842","DOI":"10.1016\/j.phymed.2019.152842","article-title":"Natural alkaloid harmine promotes degradation of alpha-synuclein via PKA-mediated ubiquitin-proteasome system activation","volume":"61","author":"Cai","year":"2019","journal-title":"Phytomedicine"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"153578","DOI":"10.1016\/j.phymed.2021.153578","article-title":"Licorine, a natural alkaloid, promotes the degradation of alpha-synuclein via PKA-mediated UPS activation in transgenic Parkinson\u2019s disease models","volume":"87","author":"Zhu","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"25009","DOI":"10.1074\/jbc.M300227200","article-title":"Alpha-synuclein is degraded by both autophagy and the proteasome","volume":"278","author":"Webb","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1126\/science.1101738","article-title":"Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy","volume":"305","author":"Cuervo","year":"2004","journal-title":"Science"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1038\/s41401-022-01039-6","article-title":"Pharmacological characterization of the small molecule 03A10 as an inhibitor of \u03b1-synuclein aggregation for Parkinson\u2019s disease treatment","volume":"44","author":"Wang","year":"2023","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Pena-Diaz, S., Garcia-Pardo, J., and Ventura, S. (2023). Development of small molecules targeting \u03b1-synuclein aggregation: A promising strategy to treat Parkinson\u2019s disease. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15030839"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s13024-018-0241-0","article-title":"Extracellular \u03b1-synuclein levels are regulated by neuronal activity","volume":"13","author":"Yamada","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.pharmthera.2016.11.010","article-title":"Prion-like mechanisms and potential therapeutic targets in neurodegenerative disorders","volume":"172","author":"Hasegawa","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1039\/D0MH01317J","article-title":"Polyphenol scaffolds in tissue engineering","volume":"8","author":"Zhang","year":"2021","journal-title":"Mater. Horiz."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/nsmb.3194","article-title":"Solid-state NMR structure of a pathogenic fibril of full-lenght human \u03b1-synuclein","volume":"23","author":"Tuttle","year":"2016","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1073\/pnas.90.4.1354","article-title":"Squalamine: An aminosterol antibiotic from the shark","volume":"90","author":"Moore","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"E1009","DOI":"10.1073\/pnas.1610586114","article-title":"A natural product inhibits the initiation of alpha-synuclein aggregation and suppresses its toxicity","volume":"114","author":"Perni","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Kazakova, O., Giniyatullina, G., Babkov, D., and Wimmer, Z. (2022). From marine metabolites to the drug of the future: Squalamine, trodusquemine, their steroid and triterpene analogues. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031075"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s40478-016-0310-y","article-title":"Fasudil attenuates aggregation of alpha-synuclein in models of Parkinson\u2019s disease","volume":"4","author":"Tatenhorst","year":"2016","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1002\/mds.108","article-title":"\u00df2-Adrenoceptor agonists and risk of Parkinson\u2019s disease","volume":"33","author":"Gronich","year":"2018","journal-title":"Mov. Disord."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"6085","DOI":"10.1021\/bi0600749","article-title":"Small molecule inhibitors of alpha-synuclein filament assembly","volume":"45","author":"Masuda","year":"2006","journal-title":"Biochemistry"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Schwab, K., Frahm, S., Horsley, D., Rickard, J.E., Melis, V., Goatman, E.A., Magbagbeolu, M., Douglas, M., Leith, M.G., and Baddeley, T.C. (2018). A protein aggregation inhibitor, leuco-methylthioninium bis (hydromethanesulfonate), decrecreases \u03b1-synuclein inclusions in a transgenic mouse model of synucleinopathy. Front. Mol. Neurosci., 10.","DOI":"10.3389\/fnmol.2017.00447"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/j.1471-4159.2006.03707.x","article-title":"Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro","volume":"97","author":"Ono","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3521","DOI":"10.1007\/s00018-018-2872-2","article-title":"Inhibition of protein misfolding and aggregation by natural phenolic compounds","volume":"75","author":"Dhouafli","year":"2018","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.biochi.2014.11.011","article-title":"Anti-fibrillation potency of caffeic acid against an antidepressant induced fibrillogenesis of human \u03b1-synuclein: Implications for Parkinson\u2019s disease","volume":"108","author":"Fazili","year":"2015","journal-title":"Biochimie"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1007\/s00401-007-0332-4","article-title":"Curcumin inhibits aggregation of alpha-synuclein","volume":"115","author":"Pandey","year":"2008","journal-title":"Acta Neuropathol."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Ardah, M.T., Paleologou, K.E., Lv, G., Khair, S.B.A., Kazim, A.S., Minhas, S.T., Al-Tel, T.H., Al-Hayani, A.A., Haque, M., and Eliezer, D. (2014). Structure activity relationship of phenolic acid inhibitors of \u03b1-synuclein fibril formation and toxicity. Front. Aging Neurosci., 6.","DOI":"10.3389\/fnagi.2014.00197"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1007\/s13311-012-0105-1","article-title":"A novel \u201cmolecular tweezer\u201d inhibitory of \u03b1-synuclein neurotoxicity in vitro and in vivo","volume":"9","author":"Prabhudesai","year":"2012","journal-title":"Neurotherapeutics"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Price, D.L., Koike, M.A., Khan, A., Wrasidlo, W., Rockenstein, E., Masliah, E., and Bonhaus, D. (2018). The small molecule alpha-synuclein misfolding inhibitor, NPT200-11, produces multiple benefits in an animal model of Parkinson\u2019s disease. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-34490-9"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1124\/pharmrev.120.000133","article-title":"Therapeutics in the pipeline targeting \u03b1-synuclein for Parkinson\u2019s disease","volume":"74","author":"Jasutkar","year":"2022","journal-title":"Pharmacol. Rev."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"5385","DOI":"10.1038\/s41467-022-32797-w","article-title":"The clinical drug candidate anle138b binds in a cavity of lipidic alpha-synuclein fibrils","volume":"13","author":"Antonschmidt","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1007\/s00401-013-1114-9","article-title":"Anle 138b: A novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson\u2019s disease","volume":"125","author":"Wagner","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1002\/mds.27562","article-title":"Anle 138b modulates alpha-synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy","volume":"34","author":"Weckbecker","year":"2019","journal-title":"Mov. Disord."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1007\/s00401-014-1265-3","article-title":"The oligomer modulator Anle 138b inhibits disease progression in a Parkinson mouse model even with treatment started after disease onset","volume":"127","author":"Levin","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"6827","DOI":"10.1021\/acs.jmedchem.1c00086","article-title":"Rationally designed preotein-based inhibitor of alpha-synuclein fibrillization in cells","volume":"64","author":"Priss","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1021\/acs.molpharmaceut.2c00548","article-title":"Structure-based discovery of small molecule inhibitors of the autocatalytic proliferation of alpha-synuclein aggregates","volume":"20","author":"Chia","year":"2023","journal-title":"Mol. Pharm."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.1016\/j.yexcr.2010.05.005","article-title":"In vitro treatments with ceftriaxone promote elimination of mutant glial fbrillary acidic protein and transcription down-regulation","volume":"316","author":"Bachetti","year":"2010","journal-title":"Exp. Cell Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.pnpbp.2009.11.021","article-title":"Ceftriaxone has a therapeutic role in Alexander disease","volume":"34","author":"Sechi","year":"2010","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1021\/cn200072h","article-title":"Ceftriaxone ameliorates motor deficits and protects dopaminergic neurons in 6-hydroxydopamine-lesioned rats","volume":"3","author":"Leung","year":"2012","journal-title":"ACS Chem. Neurosci."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Ho, Y.-J., Shen, M.-S., Tai, C.-H., Li, H.-H., Chen, J.-H., Liao, W.-C., Chiu, P.-Y., Les, I.-Y., Lin, C.-L., and Hung, C.-S. (2019). Use of ceftriaxone in treating cognitive and neuronal deficits associated with dementia with Lewy bodies. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.00507"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.1016\/j.yexcr.2012.06.008","article-title":"Beneficial effects of curcumin on GFAP filament organization and down-regulation of GFAP expression in an in vitro model of Alexander\u2019s disease","volume":"318","author":"Bachetti","year":"2012","journal-title":"Exp. Cell Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"30281","DOI":"10.1021\/acsomega.2c03534","article-title":"Curcumin interacts with alpha-synuclein condensates to inhibit amyloid aggregation under phase separation","volume":"7","author":"Xu","year":"2022","journal-title":"ACS Omega"},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Nebrisi, E.E. (2021). Neuroprotective activities of curcumin in Parkinson\u2019s disease: A review of the literature. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222011248"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"5892","DOI":"10.1074\/jbc.M404751200","article-title":"Curcumin inhibits formation of amyloid beta oligomers and fibrils, bind plaques and reduces amyloid in vivo","volume":"280","author":"Yang","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"4026","DOI":"10.1021\/acschemneuro.3c00512","article-title":"Curcumin reduces amyloid beta oligomer interactions with anionic membranes","volume":"14","author":"Sallaberry","year":"2023","journal-title":"ACS Chem. Neurosci."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"4885","DOI":"10.1038\/s41467-020-18689-x","article-title":"CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson\u2019s disease","volume":"11","author":"Faggiani","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Herrera-Vaquero, M., Bouquio, D., Kallab, M., Biggs, K., Nair, G., Ochoa, J., Heras-Garvin, A., Heid, C., Hadrovic, I., and Poewe, W. (2019). The molecular tweezer CLR01 reduces aggregated, pathologic and seeding-competent alpha-synuclein in experimental multiple system atrophy. Biochim. Biophys. Acta Mol. Basis. Dis., 1865.","DOI":"10.1016\/j.bbadis.2019.07.007"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"16958","DOI":"10.1021\/ja206279b","article-title":"Lysine-specific molecular tweezer are broad-spectruminhibitors of assembly and toxicity of amyloid proteins","volume":"133","author":"Sinha","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/s12031-015-0633-3","article-title":"Unfolded protein response pathways in neurodegenerative diseases","volume":"57","author":"Shah","year":"2015","journal-title":"J. Mol. Neurosci."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1089\/ars.2013.5593","article-title":"Targeting chelatable iron as a therapeutic modality in Parkinson\u2019s disease","volume":"21","author":"Devos","year":"2014","journal-title":"Antioxid. Redox. Signal."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Grolez, G., Moreau, C., Sablonniere, B., Garcon, G., Devedjian, J.-C., Meguig, S., Gel\u00e8, P., Delmaire, C., Bordet, R., and Defebvre, L. (2015). Ceruloplasmin activity and iron chelation treatment of patients with Parkinson\u2019s disease. BMC Neurol., 15.","DOI":"10.1186\/s12883-015-0331-3"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1038\/s41598-017-01402-2","article-title":"Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson\u2019s disease","volume":"7","author":"Ward","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1056\/NEJMoa2209254","article-title":"Trial of deferiprone in Parkinson\u2019s disease","volume":"387","author":"Devos","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_122","first-page":"2","article-title":"Targeting neurons in the gastrointestinal tract to treat Parkinson\u2019s disease","volume":"1","author":"Hauser","year":"2019","journal-title":"Clin. Park. Relat. Disord."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.7326\/M22-1438","article-title":"Oral ENT-01 targets enteric neurons to treat constipation in Parkinson disease: A randomized cotrolled trial","volume":"175","author":"Camilleri","year":"2022","journal-title":"Ann. Intern. Med."},{"key":"ref_124","unstructured":"(2024, October 14). Annovis Bio Announces New Data From Phase III Parkinson\u2019s Study Highlighting Improvements in United Parkinson\u2019s Disease Rating Scale (MDS-UPDRS) and Cognition After Treatment with Buntanetap. New Release. Annovis Bio. 2 July 2024. Available online: https:\/\/www.globenewswire.com\/news-release\/2024\/07\/02\/2907365\/0\/en\/Annovis-Bio-Announces-New-Data-from-Phase-III-Parkinson-s-Study-Highlighting-Improvements-in-Unified-Parkinson-s-Disease-Rating-Scale-MDS-UPDRS-and-Cognition-after-Treatment-with-B.html."},{"key":"ref_125","unstructured":"Levin, J., Singh, N., Melbourne, S., Morgan, A., Carroll, C., Fietzek, U., Ryazanov, S., Leonov, A., Griesinger, C.H., and Schmidt, F. (2023). Anle 138b-P1-02: A randomised, double-blinded, placebo-controlled phase 1b study to investigate safety, tolerability, pharmacokinetics and pharmacodynamics of the oligomer modulator anle 138b in Parkinson\u2019s Disease [Abstract]. Mov. Disord., 38, Available online: https:\/\/www.mdsabstracts.org\/abstract\/anle138b-p1-02-a-randomised-double-blinded-placebo-controlled-phase-1b-study-to-investigate-safety-tolerability-pharmacokinetics-and-pharmacodynamics-of-the-oligomer-modulator-anle138b-in-parkins\/."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1001\/jamaneurol.2020.4725","article-title":"Efficacy of nilotinib in patients with moderately advanced Parkinson disease: A randomized clinical trial","volume":"78","author":"Simuni","year":"2021","journal-title":"JAMA Neurol."},{"key":"ref_127","unstructured":"(2024, October 14). Yumanity Therapeutics Announces Positive Top-Line Results of Phase 1b Clinical Trial for YTX-7739 in Patients with Parkinson\u2019s Disease; Company Plans to Advance Program to Phase 2. Press Release. 10 November 2021. Available online: https:\/\/www.globenewswire.com\/news-release\/2021\/11\/10\/2331322\/0\/en\/Yumanity-Therapeutics-Announces-Positive-Top-Line-Results-of-Phase-1b-Clinical-Trial-for-YTX-7739-in-Patients-with-Parkinson-s-Disease-Company-Plans-to-Advance-Program-to-Phase-2.html."},{"key":"ref_128","unstructured":"(2023). A Phase 1, Randomized, Double-Blind, Single Ascending Dose Trial of the Safety, Tolerability and Pharmacokinetics of NPT200-11 in Healthy Subjects. Clinical Trial Highlights: Individual Trials. J. Park. Dis., Available online: https:\/\/www.journalofparkinsonsdisease.com\/phase-1-randomized-double-blind-single-ascending-dose-trial-safety-tolerability-and-pharmacokinetics."},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Ni, A., and Ernst, C. (2022). Evidence that substantia nigra pars compacta dopaminergic neurons are selectively vulnerable to oxidative stress because they are highly metabolically active. Front. Cell. Neurosci., 16.","DOI":"10.3389\/fncel.2022.826193"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.1016\/j.cub.2015.07.050","article-title":"Elevated mitochondrial bioenergetics and axonal arborization size are key contributors to the vulnerability of dopamine neurons","volume":"25","author":"Pacelli","year":"2015","journal-title":"Curr. Biol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"a009290","DOI":"10.1101\/cshperspect.a009290","article-title":"Physiological phenotype and vulnerability in Parkinson\u2019s disease","volume":"2","author":"Surmeier","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1523\/JNEUROSCI.4341-06.2007","article-title":"Roles of subthresholds calcium current and sodium current in spontaneous firing of mouse midbrain dopamine neurons","volume":"27","author":"Puopolo","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"11011","DOI":"10.1523\/JNEUROSCI.2519-09.2009","article-title":"Robust pacemaking in substantia nigra dopaminergic neurons","volume":"29","author":"Guzman","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1093\/nutrit\/nuv107","article-title":"Advances in clinical determinants and neurological manifestations of B vitamin deficiency in adults","volume":"74","author":"Sechi","year":"2016","journal-title":"Nutr. Rev."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/20\/11198\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:15:44Z","timestamp":1760112944000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/20\/11198"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,18]]},"references-count":134,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["ijms252011198"],"URL":"https:\/\/doi.org\/10.3390\/ijms252011198","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,18]]}}}