Peripheral Upregulation of Parkinson’s Disease-Associated Genes Encoding α-Synuclein, β-Glucocerebrosidase, and Ceramide Glucosyltransferase in Major Depression
<p>Peripheral gene expressions of <span class="html-italic">SNCA</span> (<b>a</b>), <span class="html-italic">GBA</span> (<b>b</b>), and <span class="html-italic">UGCG</span> (<b>c</b>) were significantly higher in patients with current MDE (combined unmedicated patients (PU) and medicated patients (PM)) at inclusion compared to unaffected individuals (combined remitted patients (PR) and healthy subjects (HC)). These levels remained for <span class="html-italic">SNCA</span> (<b>d</b>) but decreased between inclusion (T1) and follow-up (T2) after on average three weeks of treatment as usual for <span class="html-italic">GBA1</span> (<b>e</b>) and <span class="html-italic">UGCG</span> (<b>f</b>) in the group of initially medicated patients. Normalized gene expression relative to reference genes is shown on a logarithmic <span class="html-italic">y</span>-axis. The numbers of individuals are provided below the <span class="html-italic">x</span>-axis. <span class="html-italic">p</span>-values from Mann–Whitney U test (<b>a</b>–<b>c</b>) and Wilcoxon test for paired values (<b>d</b>–<b>f</b>). Box plots with median and interquartile range.</p> "> Figure 2
<p>Positive correlations between depression severity assessed by HAM-D (<b>a</b>–<b>c</b>), MADRS (<b>d</b>–<b>f</b>), and STAI trait (<b>g</b>–<b>i</b>) with peripheral gene expressions of <span class="html-italic">SNCA</span>, <span class="html-italic">GBA</span>, and <span class="html-italic">UGCG</span> in patients with remitted major depressive disorder (PR) separated in female (red dots) and male (blue dots) subgroups at inclusion. Linear regression line for the combined group with 95% confidence interval and statistics (Spearman correlation, in bold for <span class="html-italic">p</span> < 0.05). Sex-stratified statistical data are in <a href="#ijms-25-03219-t003" class="html-table">Table 3</a>.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Cohort Characteristics
2.2. Elevated Gene Expression of SNCA, GBA1, and UGCG in Depressed Patients
2.3. Associations of SNCA, GBA1, and UGCG Expressions with Depression Severity and Anxiety
2.4. Associations of SNCA, GBA1, and UGCG Expressions with Routine Blood Parameters
3. Discussion
4. Materials and Methods
4.1. Study Description
4.2. Psychometric Scales
4.3. Collection and Analysis of Blood Samples
4.4. Gene Expression Analysis by Quantitative PCR
4.5. Statistics
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Malhi, G.S.; Mann, J.J. Depression. Lancet 2018, 392, 2299–2312. [Google Scholar] [CrossRef]
- Kennedy, S.H. Core symptoms of major depressive disorder: Relevance to diagnosis and treatment. Dialogues Clin. Neurosci. 2008, 10, 271–277. [Google Scholar] [CrossRef]
- Dean, J.; Keshavan, M. The neurobiology of depression: An integrated view. Asian J. Psychiatry 2017, 27, 101–111. [Google Scholar] [CrossRef]
- Schaller, G.; Sperling, W.; Richter-Schmidinger, T.; Muhle, C.; Heberlein, A.; Maihofner, C.; Kornhuber, J.; Lenz, B. Serial repetitive transcranial magnetic stimulation (rTMS) decreases BDNF serum levels in healthy male volunteers. J. Neural Transm. 2014, 121, 307–313. [Google Scholar] [CrossRef]
- Lenz, B.; Thiem, D.; Bouna-Pyrrou, P.; Muhle, C.; Stoessel, C.; Betz, P.; Kornhuber, J. Low digit ratio (2D:4D) in male suicide victims. J. Neural Transm. 2016, 123, 1499–1503. [Google Scholar] [CrossRef] [PubMed]
- van der Heijden, A.R.; Houben, T. Lipids in major depressive disorder: New kids on the block or old friends revisited? Front. Psychiatry 2023, 14, 1213011. [Google Scholar] [CrossRef] [PubMed]
- Muhle, C.; Bilbao Canalejas, R.D.; Kornhuber, J. Sphingomyelin Synthases in Neuropsychiatric Health and Disease. Neurosignals 2019, 27, 54–76. [Google Scholar] [CrossRef]
- Zoicas, I.; Muhle, C.; Schumacher, F.; Kleuser, B.; Kornhuber, J. Development of Comorbid Depression after Social Fear Conditioning in Mice and Its Effects on Brain Sphingolipid Metabolism. Cells 2023, 12, 1355. [Google Scholar] [CrossRef] [PubMed]
- Wang, M.; Yang, L.; Chen, Z.; Dai, L.; Xi, C.; Wu, X.; Wu, G.; Wang, Y.; Hu, J. Geniposide ameliorates chronic unpredictable mild stress induced depression-like behavior through inhibition of ceramide-PP2A signaling via the PI3K/Akt/GSK3beta axis. Psychopharmacology 2021, 238, 2789–2800. [Google Scholar] [CrossRef]
- Zoicas, I.; Muhle, C.; Schmidtner, A.K.; Gulbins, E.; Neumann, I.D.; Kornhuber, J. Anxiety and Depression Are Related to Higher Activity of Sphingolipid Metabolizing Enzymes in the Rat Brain. Cells 2020, 9, 1239. [Google Scholar] [CrossRef] [PubMed]
- Schumacher, F.; Edwards, M.J.; Muhle, C.; Carpinteiro, A.; Wilson, G.C.; Wilker, B.; Soddemann, M.; Keitsch, S.; Scherbaum, N.; Muller, B.W.; et al. Ceramide levels in blood plasma correlate with major depressive disorder severity and its neutralization abrogates depressive behavior in mice. J. Biol. Chem. 2022, 298, 102185. [Google Scholar] [CrossRef] [PubMed]
- Lv, H.; Wang, H.; Xie, L.; Zou, D.; Liu, P.; Hu, Z.; Ma, R.; Shi, Y.; Zheng, G.; Zhang, G. Serum ceramide concentrations are associated with depression in patients after ischemic stroke-A two-center case-controlled study. Clin. Chim. Acta 2021, 518, 110–115. [Google Scholar] [CrossRef]
- Stefanova, N.; Seppi, K.; Scherfler, C.; Puschban, Z.; Wenning, G.K. Depression in alpha-synucleinopathies: Prevalence, pathophysiology and treatment. J. Neural Transm. Suppl. 2000, 335–343. [Google Scholar] [CrossRef]
- Cong, S.; Xiang, C.; Zhang, S.; Zhang, T.; Wang, H.; Cong, S. Prevalence and clinical aspects of depression in Parkinson’s disease: A systematic review and meta-analysis of 129 studies. Neurosci. Biobehav. Rev. 2022, 141, 104749. [Google Scholar] [CrossRef] [PubMed]
- Ntetsika, T.; Papathoma, P.E.; Markaki, I. Novel targeted therapies for Parkinson’s disease. Mol. Med. 2021, 27, 17. [Google Scholar] [CrossRef] [PubMed]
- Raket, L.L.; Oudin Astrom, D.; Norlin, J.M.; Kellerborg, K.; Martinez-Martin, P.; Odin, P. Impact of age at onset on symptom profiles, treatment characteristics and health-related quality of life in Parkinson’s disease. Sci. Rep. 2022, 12, 526. [Google Scholar] [CrossRef]
- Dujardin, K.; Sgambato, V. Neuropsychiatric Disorders in Parkinson’s Disease: What Do We Know About the Role of Dopaminergic and Non-dopaminergic Systems? Front. Neurosci. 2020, 14, 25. [Google Scholar] [CrossRef]
- Spillantini, M.G.; Schmidt, M.L.; Lee, V.M.; Trojanowski, J.Q.; Jakes, R.; Goedert, M. Alpha-synuclein in Lewy bodies. Nature 1997, 388, 839–840. [Google Scholar] [CrossRef]
- Srinivasan, E.; Chandrasekhar, G.; Chandrasekar, P.; Anbarasu, K.; Vickram, A.S.; Karunakaran, R.; Rajasekaran, R.; Srikumar, P.S. Alpha-Synuclein Aggregation in Parkinson’s Disease. Front. Med. 2021, 8, 736978. [Google Scholar] [CrossRef]
- Ross, O.A.; Braithwaite, A.T.; Skipper, L.M.; Kachergus, J.; Hulihan, M.M.; Middleton, F.A.; Nishioka, K.; Fuchs, J.; Gasser, T.; Maraganore, D.M.; et al. Genomic investigation of alpha-synuclein multiplication and parkinsonism. Ann. Neurol. 2008, 63, 743–750. [Google Scholar] [CrossRef]
- Jamjoum, R.; Majumder, S.; Issleny, B.; Stiban, J. Mysterious sphingolipids: Metabolic interrelationships at the center of pathophysiology. Front. Physiol. 2023, 14, 1229108. [Google Scholar] [CrossRef]
- Alcalay, R.N.; Mallett, V.; Vanderperre, B.; Tavassoly, O.; Dauvilliers, Y.; Wu, R.Y.J.; Ruskey, J.A.; Leblond, C.S.; Ambalavanan, A.; Laurent, S.B.; et al. SMPD1 mutations, activity, and alpha-synuclein accumulation in Parkinson’s disease. Mov. Disord. 2019, 34, 526–535. [Google Scholar] [CrossRef]
- Gan-Or, Z.; Orr-Urtreger, A.; Alcalay, R.N.; Bressman, S.; Giladi, N.; Rouleau, G.A. The emerging role of SMPD1 mutations in Parkinson’s disease: Implications for future studies. Park. Relat. Disord. 2015, 21, 1294–1295. [Google Scholar] [CrossRef]
- Smith, L.; Schapira, A.H.V. GBA Variants and Parkinson Disease: Mechanisms and Treatments. Cells 2022, 11, 1261. [Google Scholar] [CrossRef]
- Klein, A.D.; Outeiro, T.F. Glucocerebrosidase mutations disrupt the lysosome and now the mitochondria. Nat. Commun. 2023, 14, 6383. [Google Scholar] [CrossRef] [PubMed]
- Zunke, F.; Moise, A.C.; Belur, N.R.; Gelyana, E.; Stojkovska, I.; Dzaferbegovic, H.; Toker, N.J.; Jeon, S.; Fredriksen, K.; Mazzulli, J.R. Reversible Conformational Conversion of alpha-Synuclein into Toxic Assemblies by Glucosylceramide. Neuron 2018, 97, 92–107.e110. [Google Scholar] [CrossRef] [PubMed]
- Ishibashi, Y.; Ito, M.; Hirabayashi, Y. The sirtuin inhibitor cambinol reduces intracellular glucosylceramide with ceramide accumulation by inhibiting glucosylceramide synthase. Biosci. Biotechnol. Biochem. 2020, 84, 2264–2272. [Google Scholar] [CrossRef]
- Kiechle, M.; Grozdanov, V.; Danzer, K.M. The Role of Lipids in the Initiation of alpha-Synuclein Misfolding. Front. Cell Dev. Biol. 2020, 8, 562241. [Google Scholar] [CrossRef]
- Munoz, S.S.; Petersen, D.; Marlet, F.R.; Kucukkose, E.; Galvagnion, C. The interplay between Glucocerebrosidase, alpha-synuclein and lipids in human models of Parkinson’s disease. Biophys. Chem. 2021, 273, 106534. [Google Scholar] [CrossRef]
- Mazzulli, J.R.; Xu, Y.H.; Sun, Y.; Knight, A.L.; McLean, P.J.; Caldwell, G.A.; Sidransky, E.; Grabowski, G.A.; Krainc, D. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 2011, 146, 37–52. [Google Scholar] [CrossRef] [PubMed]
- Kalia, L.V.; Lang, A.E. Parkinson’s disease. Lancet 2015, 386, 896–912. [Google Scholar] [CrossRef] [PubMed]
- Fahn, S. Description of Parkinson’s disease as a clinical syndrome. Ann. N. Y. Acad. Sci. 2003, 991, 1–14. [Google Scholar] [CrossRef] [PubMed]
- Chaudhuri, K.R.; Schapira, A.H. Non-motor symptoms of Parkinson’s disease: Dopaminergic pathophysiology and treatment. Lancet Neurol. 2009, 8, 464–474. [Google Scholar] [CrossRef] [PubMed]
- Todorova, A.; Jenner, P.; Ray Chaudhuri, K. Non-motor Parkinson’s: Integral to motor Parkinson’s, yet often neglected. Pract. Neurol. 2014, 14, 310–322. [Google Scholar] [CrossRef] [PubMed]
- Bareeqa, S.B.; Samar, S.S.; Kamal, S.; Masood, Y.; Allahyar; Ahmed, S.I.; Hayat, G. Prodromal depression and subsequent risk of developing Parkinson’s disease: A systematic review with meta-analysis. Neurodegener. Dis. Manag. 2022, 12, 155–164. [Google Scholar] [CrossRef] [PubMed]
- Wang, S.; Mao, S.; Xiang, D.; Fang, C. Association between depression and the subsequent risk of Parkinson’s disease: A meta-analysis. Prog. Neuropsychopharmacol. Biol. Psychiatry 2018, 86, 186–192. [Google Scholar] [CrossRef]
- Allain, H.; Schuck, S.; Mauduit, N. Depression in Parkinson’s disease. BMJ 2000, 320, 1287–1288. [Google Scholar] [CrossRef]
- Paciotti, S.; Albi, E.; Parnetti, L.; Beccari, T. Lysosomal Ceramide Metabolism Disorders: Implications in Parkinson’s Disease. J. Clin. Med. 2020, 9, 594. [Google Scholar] [CrossRef]
- Motyl, J.A.; Strosznajder, J.B.; Wencel, A.; Strosznajder, R.P. Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease. Int. J. Mol. Sci. 2021, 22, 6277. [Google Scholar] [CrossRef]
- Julian, L.J. Measures of anxiety: State-Trait Anxiety Inventory (STAI), Beck Anxiety Inventory (BAI), and Hospital Anxiety and Depression Scale-Anxiety (HADS-A). Arthritis Care Res. 2011, 63 (Suppl. S11), S467–S472. [Google Scholar] [CrossRef]
- Rotter, A.; Lenz, B.; Pitsch, R.; Richter-Schmidinger, T.; Kornhuber, J.; Rhein, C. Alpha-Synuclein RNA Expression is Increased in Major Depression. Int. J. Mol. Sci. 2019, 20, 2029. [Google Scholar] [CrossRef] [PubMed]
- Ishiguro, M.; Baba, H.; Maeshima, H.; Shimano, T.; Inoue, M.; Ichikawa, T.; Yasuda, S.; Shukuzawa, H.; Suzuki, T.; Arai, H. Increased Serum Levels of alpha-Synuclein in Patients With Major Depressive Disorder. Am. J. Geriatr. Psychiatry 2019, 27, 280–286. [Google Scholar] [CrossRef] [PubMed]
- Frieling, H.; Gozner, A.; Romer, K.D.; Wilhelm, J.; Hillemacher, T.; Kornhuber, J.; de Zwaan, M.; Jacoby, G.E.; Bleich, S. Alpha-synuclein mRNA levels correspond to beck depression inventory scores in females with eating disorders. Neuropsychobiology 2008, 58, 48–52. [Google Scholar] [CrossRef] [PubMed]
- Wersinger, C.; Rusnak, M.; Sidhu, A. Modulation of the trafficking of the human serotonin transporter by human alpha-synuclein. Eur. J. Neurosci. 2006, 24, 55–64. [Google Scholar] [CrossRef] [PubMed]
- Jeannotte, A.M.; Sidhu, A. Regulation of the norepinephrine transporter by alpha-synuclein-mediated interactions with microtubules. Eur. J. Neurosci. 2007, 26, 1509–1520. [Google Scholar] [CrossRef]
- Jeannotte, A.M.; McCarthy, J.G.; Redei, E.E.; Sidhu, A. Desipramine modulation of alpha-, gamma-synuclein, and the norepinephrine transporter in an animal model of depression. Neuropsychopharmacology 2009, 34, 987–998. [Google Scholar] [CrossRef] [PubMed]
- Sardi, S.P.; Clarke, J.; Viel, C.; Chan, M.; Tamsett, T.J.; Treleaven, C.M.; Bu, J.; Sweet, L.; Passini, M.A.; Dodge, J.C.; et al. Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies. Proc. Natl. Acad. Sci. USA 2013, 110, 3537–3542. [Google Scholar] [CrossRef]
- Migdalska-Richards, A.; Daly, L.; Bezard, E.; Schapira, A.H. Ambroxol effects in glucocerebrosidase and alpha-synuclein transgenic mice. Ann. Neurol. 2016, 80, 766–775. [Google Scholar] [CrossRef]
- Kaiser, T.; Herzog, P.; Voderholzer, U.; Brakemeier, E.L. Unraveling the comorbidity of depression and anxiety in a large inpatient sample: Network analysis to examine bridge symptoms. Depress. Anxiety 2021, 38, 307–317. [Google Scholar] [CrossRef]
- Lamers, F.; van Oppen, P.; Comijs, H.C.; Smit, J.H.; Spinhoven, P.; van Balkom, A.J.; Nolen, W.A.; Zitman, F.G.; Beekman, A.T.; Penninx, B.W. Comorbidity patterns of anxiety and depressive disorders in a large cohort study: The Netherlands Study of Depression and Anxiety (NESDA). J. Clin. Psychiatry 2011, 72, 341–348. [Google Scholar] [CrossRef]
- Brainstorm, C.; Anttila, V.; Bulik-Sullivan, B.; Finucane, H.K.; Walters, R.K.; Bras, J.; Duncan, L.; Escott-Price, V.; Falcone, G.J.; Gormley, P.; et al. Analysis of shared heritability in common disorders of the brain. Science 2018, 360, eaap8757. [Google Scholar] [CrossRef]
- Kessler, R.C.; Berglund, P.; Demler, O.; Jin, R.; Merikangas, K.R.; Walters, E.E. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 2005, 62, 593–602. [Google Scholar] [CrossRef] [PubMed]
- Kulisevsky, J.; Pagonabarraga, J.; Pascual-Sedano, B.; Garcia-Sanchez, C.; Gironell, A.; Trapecio Group, S. Prevalence and correlates of neuropsychiatric symptoms in Parkinson’s disease without dementia. Mov. Disord. 2008, 23, 1889–1896. [Google Scholar] [CrossRef]
- Bellomo, G.; Bologna, S.; Cerofolini, L.; Paciotti, S.; Gatticchi, L.; Ravera, E.; Parnetti, L.; Fragai, M.; Luchinat, C. Dissecting the Interactions between Human Serum Albumin and alpha-Synuclein: New Insights on the Factors Influencing alpha-Synuclein Aggregation in Biological Fluids. J. Phys. Chem. B 2019, 123, 4380–4386. [Google Scholar] [CrossRef] [PubMed]
- Goldknopf, I.L.; Bryson, J.K.; Strelets, I.; Quintero, S.; Sheta, E.A.; Mosqueda, M.; Park, H.R.; Appel, S.H.; Shill, H.; Sabbagh, M.; et al. Abnormal serum concentrations of proteins in Parkinson’s disease. Biochem. Biophys. Res. Commun. 2009, 389, 321–327. [Google Scholar] [CrossRef] [PubMed]
- Rcom-H’cheo-Gauthier, A.N.; Osborne, S.L.; Meedeniya, A.C.; Pountney, D.L. Calcium: Alpha-Synuclein Interactions in Alpha-Synucleinopathies. Front. Neurosci. 2016, 10, 570. [Google Scholar] [CrossRef]
- Emad, E.M.; Elmotaym, A.S.E.; Ghonemy, M.m.A.; Badawy, A.E. The effect of hypocalcemia on motor symptoms of Parkinson’s disease. Egypt. J. Neurol. Psychiatry Neurosurg. 2022, 58, 76. [Google Scholar] [CrossRef]
- Ma, L.; Xu, Y.; Wang, G.; Li, R. What do we know about sex differences in depression: A review of animal models and potential mechanisms. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2019, 89, 48–56. [Google Scholar] [CrossRef]
- von Zimmermann, C.; Hubner, M.; Muhle, C.; Muller, C.P.; Weinland, C.; Kornhuber, J.; Lenz, B. Masculine depression and its problem behaviors: Use alcohol and drugs, work hard, and avoid psychiatry! Eur. Arch. Psychiatry Clin. Neurosci. 2023, 274, 321–333. [Google Scholar] [CrossRef]
- von Zimmermann, C.; Bruckner, L.; Muhle, C.; Weinland, C.; Kornhuber, J.; Lenz, B. Bioimpedance Body Measures and Serum Lipid Levels in Masculine Depression. Front. Psychiatry 2022, 13, 794351. [Google Scholar] [CrossRef]
- Sedlinska, T.; Muhle, C.; Richter-Schmidinger, T.; Weinland, C.; Kornhuber, J.; Lenz, B. Male depression syndrome is characterized by pronounced Cluster B personality traits. J. Affect. Disord. 2021, 292, 725–732. [Google Scholar] [CrossRef]
- Yang, C.; Pan, R.Y.; Guan, F.; Yuan, Z. Lactate metabolism in neurodegenerative diseases. Neural Regen. Res. 2024, 19, 69–74. [Google Scholar] [CrossRef]
- Yao, Q.; Liu, H.; Li, Y. Low levels of serum LDH are associated with depression and suicide attempts. Gen. Hosp. Psychiatry 2022, 79, 42–49. [Google Scholar] [CrossRef]
- Abounit, S.; Bousset, L.; Loria, F.; Zhu, S.; de Chaumont, F.; Pieri, L.; Olivo-Marin, J.C.; Melki, R.; Zurzolo, C. Tunneling nanotubes spread fibrillar alpha-synuclein by intercellular trafficking of lysosomes. EMBO J. 2016, 35, 2120–2138. [Google Scholar] [CrossRef] [PubMed]
- White, A.J.; Wijeyekoon, R.S.; Scott, K.M.; Gunawardana, N.P.; Hayat, S.; Solim, I.H.; McMahon, H.T.; Barker, R.A.; Williams-Gray, C.H. The Peripheral Inflammatory Response to Alpha-Synuclein and Endotoxin in Parkinson’s Disease. Front. Neurol. 2018, 9, 946. [Google Scholar] [CrossRef] [PubMed]
- Li, G.; Liu, J.; Guo, M.; Gu, Y.; Guan, Y.; Shao, Q.; Ma, W.; Ji, X. Chronic hypoxia leads to cognitive impairment by promoting HIF-2alpha-mediated ceramide catabolism and alpha-synuclein hyperphosphorylation. Cell Death Discov. 2022, 8, 473. [Google Scholar] [CrossRef] [PubMed]
- Takubo, H.; Shimoda-Matsubayashi, S.; Mizuno, Y. Serum creatine kinase is elevated in patients with Parkinson’s disease: A case controlled study. Park. Relat. Disord. 2003, 9 (Suppl. S1), S43–S46. [Google Scholar] [CrossRef]
- Xu, J.; Fu, X.; Pan, M.; Zhou, X.; Chen, Z.; Wang, D.; Zhang, X.; Chen, Q.; Li, Y.; Huang, X.; et al. Mitochondrial Creatine Kinase is Decreased in the Serum of Idiopathic Parkinson’s Disease Patients. Aging Dis. 2019, 10, 601–610. [Google Scholar] [CrossRef]
- Aminabad, E.D.; Hasanzadeh, M.; Ahmadalipour, A.; Mahmoudi, T.; Feizi, M.A.H.; Safaralizadeh, R.; Mobed, A. Sensitive electrochemical recognition of alpha-synuclein protein in human plasma samples using bioconjugated gold nanoparticles: An innovative immuno-platform to assist in the early stage identification of Parkinson’s disease by biosensor technology. J. Mol. Recognit. 2023, 36, e2952. [Google Scholar] [CrossRef]
- Aminabad, E.D.; Mobed, A.; Hasanzadeh, M.; Hosseinpour Feizi, M.A.; Safaralizadeh, R.; Seidi, F. Sensitive immunosensing of alpha-synuclein protein in human plasma samples using gold nanoparticles conjugated with graphene: An innovative immuno-platform towards early stage identification of Parkinson’s disease using point of care (POC) analysis. RSC Adv. 2022, 12, 4346–4357. [Google Scholar] [CrossRef]
- Youssef, P.; Kim, W.S.; Halliday, G.M.; Lewis, S.J.G.; Dzamko, N. Comparison of Different Platform Immunoassays for the Measurement of Plasma Alpha-Synuclein in Parkinson’s Disease Patients. J. Park. Dis. 2021, 11, 1761–1772. [Google Scholar] [CrossRef]
- Zheng, H.; Xie, Z.; Zhang, X.; Mao, J.; Wang, M.; Wei, S.; Fu, Y.; Zheng, H.; He, Y.; Chen, H.; et al. Investigation of alpha-Synuclein Species in Plasma Exosomes and the Oligomeric and Phosphorylated alpha-Synuclein as Potential Peripheral Biomarker of Parkinson’s Disease. Neuroscience 2021, 469, 79–90. [Google Scholar] [CrossRef]
- Muhle, C.; Kornhuber, J. Characterization of a Neutral Sphingomyelinase Activity in Human Serum and Plasma. Int. J. Mol. Sci. 2023, 24, 2467. [Google Scholar] [CrossRef]
- Cataldi, S.; Arcuri, C.; Hunot, S.; Legeron, F.P.; Mecca, C.; Garcia-Gil, M.; Lazzarini, A.; Codini, M.; Beccari, T.; Tasegian, A.; et al. Neutral Sphingomyelinase Behaviour in Hippocampus Neuroinflammation of MPTP-Induced Mouse Model of Parkinson’s Disease and in Embryonic Hippocampal Cells. Mediat. Inflamm. 2017, 2017, 2470950. [Google Scholar] [CrossRef]
- Kim, M.J.; Jeon, S.; Burbulla, L.F.; Krainc, D. Acid ceramidase inhibition ameliorates alpha-synuclein accumulation upon loss of GBA1 function. Hum. Mol. Genet. 2018, 27, 1972–1988. [Google Scholar] [CrossRef]
- Kind, L.; Luttenberger, K.; Lessmann, V.; Dorscht, L.; Muhle, C.; Muller, C.P.; Siegmann, E.M.; Schneider, S.; Kornhuber, J. New ways to cope with depression-study protocol for a randomized controlled mixed methods trial of bouldering psychotherapy (BPT) and mental model therapy (MMT). Trials 2023, 24, 602. [Google Scholar] [CrossRef]
- Haroon, E.; Daguanno, A.W.; Woolwine, B.J.; Goldsmith, D.R.; Baer, W.M.; Wommack, E.C.; Felger, J.C.; Miller, A.H. Antidepressant treatment resistance is associated with increased inflammatory markers in patients with major depressive disorder. Psychoneuroendocrinology 2018, 95, 43–49. [Google Scholar] [CrossRef]
- Correia, A.S.; Cardoso, A.; Vale, N. Highlighting Immune System and Stress in Major Depressive Disorder, Parkinson’s, and Alzheimer’s Diseases, with a Connection with Serotonin. Int. J. Mol. Sci. 2021, 22, 8525. [Google Scholar] [CrossRef] [PubMed]
- Kalinichenko, L.S.; Kohl, Z.; Muhle, C.; Hassan, Z.; Hahn, A.; Schmitt, E.M.; Macht, K.; Stoyanov, L.; Moghaddami, S.; Bilbao, R.; et al. Sex-specific pleiotropic changes in emotional behavior and alcohol consumption in human alpha-synuclein A53T transgenic mice during early adulthood. J. Neurochem. 2024, 168, 269–287. [Google Scholar] [CrossRef] [PubMed]
- Muhle, C.; Wagner, C.J.; Farber, K.; Richter-Schmidinger, T.; Gulbins, E.; Lenz, B.; Kornhuber, J. Secretory Acid Sphingomyelinase in the Serum of Medicated Patients Predicts the Prospective Course of Depression. J. Clin. Med. 2019, 8, 846. [Google Scholar] [CrossRef] [PubMed]
- Wagner, C.J.; Musenbichler, C.; Bohm, L.; Farber, K.; Fischer, A.I.; von Nippold, F.; Winkelmann, M.; Richter-Schmidinger, T.; Muhle, C.; Kornhuber, J.; et al. LDL cholesterol relates to depression, its severity, and the prospective course. Prog. Neuropsychopharmacol. Biol. Psychiatry 2019, 92, 405–411. [Google Scholar] [CrossRef]
- von Zimmermann, C.; Winkelmann, M.; Richter-Schmidinger, T.; Muhle, C.; Kornhuber, J.; Lenz, B. Physical Activity and Body Composition Are Associated With Severity and Risk of Depression, and Serum Lipids. Front. Psychiatry 2020, 11, 494. [Google Scholar] [CrossRef]
- von Zimmermann, C.; Bohm, L.; Richter-Schmidinger, T.; Kornhuber, J.; Lenz, B.; Muhle, C. Ex vivo glucocorticoid receptor-mediated IL-10 response predicts the course of depression severity. J. Neural Transm. 2021, 128, 95–104. [Google Scholar] [CrossRef]
- Swoboda, C.; Deloch, L.; von Zimmermann, C.; Richter-Schmidinger, T.; Lenz, B.; Kornhuber, J.; Muhle, C. Macrophage Migration Inhibitory Factor in Major Depressive Disorder: A Multilevel Pilot Study. Int. J. Mol. Sci. 2022, 23, 5460. [Google Scholar] [CrossRef]
- Hamilton, M. A rating scale for depression. J. Neurol Neurosurg. Psychiatry 1960, 23, 56–62. [Google Scholar] [CrossRef]
- Montgomery, S.A.; Asberg, M. A new depression scale designed to be sensitive to change. Br. J. Psychiatry 1979, 134, 382–389. [Google Scholar] [CrossRef] [PubMed]
- Beck, A.T.; Steer, R.A.; Brown, G.K. Manual for the Beck Depression Inventory-II; Psychological Corporation: San Antonio, TX, USA, 1996; Volume 1. [Google Scholar]
- Spielberger, C.D.; Gorsuch, L.; Laux, L.; Glanzmann, P.; Schaffner, P. Das State-Trait-Angstinventar: STAI; Beltz Test: Göttingen, Germany, 2001. [Google Scholar]
- ISO 15189:2022; Medical Laboratories—Requirements for Quality and Competence. International Organization for Standardization: Geneva, Switzerland, 2022.
- Taylor, S.; Wakem, M.; Dijkman, G.; Alsarraj, M.; Nguyen, M. A practical approach to RT-qPCR-Publishing data that conform to the MIQE guidelines. Methods 2010, 50, S1–S5. [Google Scholar] [CrossRef] [PubMed]
- Tran, A.A.; De Smet, M.; Grant, G.D.; Khoo, T.K.; Pountney, D.L. Investigating the Convergent Mechanisms between Major Depressive Disorder and Parkinson’s Disease. Complex Psychiatry 2021, 6, 47–61. [Google Scholar] [CrossRef] [PubMed]
- Custodia, A.; Aramburu-Nunez, M.; Correa-Paz, C.; Posado-Fernandez, A.; Gomez-Larrauri, A.; Castillo, J.; Gomez-Munoz, A.; Sobrino, T.; Ouro, A. Ceramide Metabolism and Parkinson’s Disease-Therapeutic Targets. Biomolecules 2021, 11, 945. [Google Scholar] [CrossRef] [PubMed]
Unmed. Patients | Medicated Patients | Remitted Patients | Healthy Controls | |||||||
---|---|---|---|---|---|---|---|---|---|---|
n | Median (IQR) | n | Median (IQR) | n | Median (IQR) | n | Median (IQR) | p (Sex) | p (Groups) | |
Age (years) | 63 | 46 (33–53) | 66 | 46 (33–54) | 38 | 50 (46–58) | 60 | 41 (32–54) | 0.081 | 0.502 |
Education (years) | 56 | 15 (13–18) | 58 | 14 (13–16) | 34 | 14 (13–16) | 50 | 16 (13–18) | 0.008 | 0.594 |
BMI (kg/m2) | 63 | 25.1 (22.5–27.4) | 66 | 28.5 (24.4–30.4) | 38 | 25.7 (23.0–29.1) | 60 | 24.5 (23.0–27.8) | 0.005 | 0.190 |
HAM-D T1 | 63 | 21 (19–24) | 66 | 23 (20–26) | 38 | 2 (0–3) | 60 | 0 (0–2) | 0.743 | <0.001 |
HAM-D T2 | 59 | 18 (14–20) | 60 | 15 (10–22) | 0.048 | |||||
MADRS T1 | 63 | 26 (23–28) | 66 | 28 (24–34) | 38 | 1 (0–3) | 60 | 0 (0–2) | 0.950 | <0.001 |
MADRS T2 | 59 | 21 (18–25) | 60 | 18 (13–26) | 0.052 | |||||
BDI-II T1 | 63 | 28 (22–34) | 66 | 29 (24–35) | 38 | 3 (0–3) | 60 | 2 (0–3) | 0.528 | <0.001 |
BDI-II T2 | 59 | 19 (15–25) | 60 | 20 (13–31) | 0.009 | |||||
STAI state T1 | 63 | 50 (40–56) | 66 | 54 (43–63) | 38 | 32 (26–36) | 60 | 28 (26–31) | 0.910 | <0.001 |
STAI state T2 | 59 | 46 (37–52) | 60 | 47 (42–57) | 0.819 | |||||
STAI trait mean | 63 | 60 (55–66) | 66 | 58 (52–66) | 38 | 34 (27–40) | 60 | 28 (25–33) | 0.624 | <0.001 |
SNCA expression (AU) T1 | 63 | 17.7 (9.8–26.3) | 66 | 21.2 (10.1–36.2) | 38 | 13.8 (7.6–34.2) | 59 | 15.6 (6.7–29.3) | 0.666 | 0.036 |
SNCA expression (AU) T2 | 55 | 14.2 (8.2–25.5) | 60 | 20.3 (9.9–31.3) | 0.420 | |||||
SNCA expression rel. change | 55 | −0.016 (−0.450–0.656) | 60 | −0.044 (−0.370–0.556) | 0.322 | |||||
GBA1 expression (AU) T1 | 63 | 0.237 (0.136–0.474) | 64 | 0.302 (0.177–0.458) | 38 | 0.194 (0.072–0.395) | 59 | 0.178 (0.081–0.429) | 0.570 | 0.014 |
GBA1 expression (AU) T2 | 56 | 0.208 (0.099–0.394) | 57 | 0.245 (0.149–0.493) | 0.255 | |||||
GBA1 expression rel. change | 56 | −0.131 (−0.587–0.873) | 56 | −0.210 (−0.444–0.201) | 0.435 | |||||
UGCG exp. (AU) T1 | 63 | 0.136 (0.070–0.200) | 64 | 0.174 (0.105–0.291) | 38 | 0.093 (0.048–0.173) | 57 | 0.089 (0.047–0.215) | 0.123 | <0.001 |
UGCG exp. (AU) T2 | 57 | 0.122 (0.072–0.229) | 57 | 0.147 (0.092–0.271) | 0.147 | |||||
UGCG exp rel. change | 57 | 0.173 (−0.577–1.018) | 55 | −0.227 (−0.499–0.178) | 0.431 |
SNCA Expression in PU + PM | HAM-D | MADRS | BDI-II | ||||
---|---|---|---|---|---|---|---|
n | ρ | p | ρ | p | ρ | p | |
All | 129 | 0.016 | 0.855 | 0.107 | 0.227 | 0.190 | 0.031 |
Female | 69 | 0.150 | 0.219 | 0.197 | 0.105 | 0.256 | 0.034 |
Male | 60 | −0.130 | 0.323 | −0.030 | 0.818 | 0.046 | 0.726 |
Remitted | HAM-D | MADRS | BDI-II | STAI Trait | ||||||
---|---|---|---|---|---|---|---|---|---|---|
Patients | n | ρ | p | ρ | p | ρ | p | ρ | p | |
SNCA | All | 38 | 0.363 | 0.025 | 0.350 | 0.031 | 0.186 | 0.263 | 0.325 | 0.047 |
Female | 28 | 0.366 | 0.056 | 0.387 | 0.042 | 0.237 | 0.224 | 0.338 | 0.079 | |
Male | 10 | 0.331 | 0.351 | 0.259 | 0.471 | −0.032 | 0.931 | 0.273 | 0.446 | |
GBA1 | All | 38 | 0.336 | 0.039 | 0.404 | 0.012 | 0.278 | 0.091 | 0.313 | 0.056 |
Female | 28 | 0.288 | 0.137 | 0.390 | 0.040 | 0.295 | 0.128 | 0.231 | 0.237 | |
Male | 10 | 0.248 | 0.490 | 0.259 | 0.471 | 0.127 | 0.726 | 0.358 | 0.310 | |
UGCG | All | 38 | 0.327 | 0.045 | 0.380 | 0.019 | 0.262 | 0.111 | 0.404 | 0.012 |
Female | 28 | 0.344 | 0.073 | 0.475 | 0.011 | 0.308 | 0.111 | 0.385 | 0.043 | |
Male | 10 | 0.133 | 0.713 | 0.032 | 0.929 | −0.025 | 0.944 | 0.248 | 0.489 |
SNCA | GBA1 | UGCG | ||||||
---|---|---|---|---|---|---|---|---|
n | ρ | p | ρ | p | ρ | p | ||
LDH | All | 38 | −0.346 | 0.033 | −0.421 | 0.008 | −0.377 | 0.020 |
Remitted | Female | 28 | −0.180 | 0.359 | −0.283 | 0.144 | −0.250 | 0.199 |
Patients | Male | 10 | −0.869 | 0.001 | −0.888 | 0.001 | −0.699 | 0.024 |
CK | All | 97 | −0.115 | 0.261 | −0.183 | 0.073 | −0.154 | 0.136 |
Healthy controls | Female | 58 | −0.000 | 0.999 | −0.033 | 0.809 | −0.033 | 0.806 |
and remitted patients | Male | 39 | −0.353 | 0.027 | −0.384 | 0.015 | −0.379 | 0.019 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Brazdis, R.-M.; von Zimmermann, C.; Lenz, B.; Kornhuber, J.; Mühle, C. Peripheral Upregulation of Parkinson’s Disease-Associated Genes Encoding α-Synuclein, β-Glucocerebrosidase, and Ceramide Glucosyltransferase in Major Depression. Int. J. Mol. Sci. 2024, 25, 3219. https://doi.org/10.3390/ijms25063219
Brazdis R-M, von Zimmermann C, Lenz B, Kornhuber J, Mühle C. Peripheral Upregulation of Parkinson’s Disease-Associated Genes Encoding α-Synuclein, β-Glucocerebrosidase, and Ceramide Glucosyltransferase in Major Depression. International Journal of Molecular Sciences. 2024; 25(6):3219. https://doi.org/10.3390/ijms25063219
Chicago/Turabian StyleBrazdis, Razvan-Marius, Claudia von Zimmermann, Bernd Lenz, Johannes Kornhuber, and Christiane Mühle. 2024. "Peripheral Upregulation of Parkinson’s Disease-Associated Genes Encoding α-Synuclein, β-Glucocerebrosidase, and Ceramide Glucosyltransferase in Major Depression" International Journal of Molecular Sciences 25, no. 6: 3219. https://doi.org/10.3390/ijms25063219