Parkin Deficiency Appears Not to Be Associated with Cardiac Damage in Parkinson's Disease
2021-01-01

We read with great interest the study “Subclinical Cardiac Microdamage, Motor Severity, and Cognition in Parkinson's Disease” by Choe and colleagues.1 The authors demonstrated an increase of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with idiopathic Parkinson's disease (IPD) and an association of NT-proBNP and Troponin I with impaired motor and cognitive function. The authors suggested shared pathophysiological mechanisms of PD and heart disease based on overlapping molecular pathways and high energy demand in dopaminergic neurons and cardiomyocytes, pointing to a potential role of mitochondria because their integrity is crucial for proper energy production. Because mutations in Parkin cause mitochondrial dysfunction,2 we aimed to elucidate the impact of Parkin deficiency on induced pluripotent stem cell (iPSC)-derived cardiomyocytes obtained from PD patients with biallelic Parkin mutations (Parkin-PD), Parkin-mutation-negative IPD patients, and healthy controls (HC, n = 2 per group) (Fig. 1A; Supplementary Table S1). Analyzing cell-specific protein levels by western blotting, we found no significant difference of Troponin T (TropT) levels in cardiomyocytes from Parkin-PD compared to HC or IPD patients (Fig. 1B). Additionally, we investigated TropT levels in serum samples from Parkin-PD (n = 22, Supplementary Table S2), IPD patients (n = 30), and controls (n = 38) (for demographics see Supplementary Table S3). We detected decreased unadjusted TropT levels in Parkin-PD compared to HCs, whereas IPD patients exhibited the highest TropT levels (Fig. 1C). Because TropT increases with age in all groups (Spearman's correlation, n = 90, r = 0.538, P < 0.01) and Parkin-PD were younger at examination than IPD and HC, we performed a sensitivity analysis investigating differences in TropT levels taking age into account. We found no differences between the three study groups (Fig. 1D). Data on potentially confounding cardiovascular conditions was limited. Our study provides evidence for normal TropT levels in Parkin-linked PD in cardiomyocytes and sera, suggesting that Parkin deficiency may not be associated with cardiac damage in PD. Therefore, our findings point to mechanisms other than mitochondrial dysfunction that may explain the link between PD and heart involvement in IPD patients. Supporting this notion, the absence of any acutely deleterious effect of a conditional cardiac-specific Parkin deletion in adult mouse hearts indicates that Parkin has a limited role in normal homeostatic cardiac mitochondrial quality control.3 Our results are in line with studies reporting more severely impaired cardiac autonomic innervation in IPD than in Parkin-PD, possibly indicating no or less α-synuclein deposition in cardiac tissue in Parkin-PD.4 Interestingly, metabolic syndrome is not only a risk factor for cardiovascular diseases but has been positively associated with the development of IPD.5 Therefore, our findings indicate that in contrast to IPD, cardiovascular metabolic abnormalities do not appear to play a major role in the etiology of Parkin-PD. To conclude, we did not find evidence for subclinical cardiac damage in Parkin-PD based on TropT analysis. Further functional studies investigating IPD and cardiac disease are warranted, combined with in-depth epidemiological studies, including confounding factors and appropriate control groups. We thank the participants for participation and donating their biomaterials for research purposes. Moreover, we thank the LADR Centrallab Dr. Kramer and colleagues, Geesthacht, Germany, and especially Dr. Bätz, for technical advice and support for measurements of serum TropT levels. Open Access funding enabled and organized by ProjektDEAL. C.K. was supported by SysMedPD (European Union's Horizon 2020 research and innovation program under grant agreement 668738). C.K., I.R.K., N.B., M.K., K.L, and P.S. were supported by the German Research Foundation (FOR2488). E.M.V. received funding from the Italian Ministry of Health (Ricerca Corrente 2020), and CARIPLO Foundation (grant 2017-0575). The work was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement number 115439, resources of which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007e2013) and EFPIA companies’ in-kind contribution. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique. M.T.W.: 1A, 1B, 1C, 2A, 2B, 2C, 3B M.B.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B I.R.K.: 1C, 2A, 2B, 2C, 3B I.L.: 1C, 2C, 3B A.B.: 1C, 2C, 3B M.K.: 1C, 2C, 3B K.L.: 1C, 2C, 3B K.B.: 1C, 2C, 3B E.M.V.: 1C, 2C, 3B C.K.: 1A, 1B, 1C, 2C, 3B N.B.: 1A, 1B, 1C, 2C, 3B P.S.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, B M.T.W. is employed by the University of Lübeck. M.B. is employed by the University of Lübeck. I.R.K. received grants from the German Research Foundation (DFG), BMBF, and German Cancer Aid and is employed by the University of Lübeck. I.L. is employed by the University of Lübeck. A.B. received grants from German Research Foundation (DFG), and intramural funds from the University of Lübeck (Clinician Scientist) and is employed by the University of Lübeck. M.K. is employed by the University of Lübeck. K.L. received grants from German Research Foundation (DFG), Damp Stiftung, and the Movement Disorders Society (MDS) and is employed by the University of Lübeck. K.B. received honoraria from Abbvie, Lundbeck, UCB, and Zambon. She also received grants from the University of Tübingen (Clinician Scientist), the German Society of Parkinson's disease (dpv), the Michael J. Fox Foundation (MJFF), and the German Centre for Neurodegenerative Diseases (DZNE, MIGAP) and is employed by the University of Tübingen. E.M.V. received fees from Consultancies from Expert panelist for the International Parkinson and Movement Disorder Society, honoraria's from Zambon, and travel grants from the European Society of Human Genetics. E.M.V. is also the Associate Editor of Journal of Medical Genetics, the Section Editor of Pediatric Research, Member of the Editorial Board of Movement Disorders Clinical Practice, Research support from the Italian Ministry of Health, CARIPLO Foundation, Pierfranco and Luisa Mariani Foundation and is employed by the University of Pavia. C.K. received fees from consultancies as a Medical consultant to Centogene for genetic testing for movement disorders (except parkinsonism) and dementia. She also received honoria from the Scientific Advisory Board of the Else Kroener Fresenius Foundation and grants from the Movement Disorder Society (MDS), Michael J. Fox Foundation (MJFF), BMBF, and European Commission, and intramural funds from the University of Lübeck. She also receives royalties from Oxford University Press and is employed by the University of Lübeck. N.B. received fees from consultancies from Censa and Centogene and grants from German Research Foundation (DFG; BR4328/2-2, GRK1957) and Collaborative Center for X-linked Dystonia-Parkinsonism and is employed by the University of Lübeck. P.S. received grants from German Research Foundation (DFG; SE 2608/2-2; SE 2608/5-2) and Collaborative Center for X-linked Dystonia-Parkinsonism and is employed by the University of Lübeck. Appendix S1. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.