Abstract
The substantial contributions of Dr. Gerald Stern to past and current treatments for Parkinson’s disease patients are reviewed, which form the foundation for an evaluation of future options to control symptoms and halt progression of the disease. These opportunities will depend on a greater understanding of the relative contributions of the environment, genetic and epigenetic influences to disease onset, and promise to emerge as strategies for improving mitochondrial function, halting accumulation of synuclein and neuromelanin, in addition to refinement of stem cell and gene therapies. Such advances will be achieved through deployment of improved models for the disease.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abbott A (2014) Fetal-cell revival for Parkinson's. Nature 510:195–196. https://doi.org/10.1038/510195a
Aly AE, Waszczak BL (2015) Intranasal gene delivery for treating Parkinson's disease: overcoming the blood-brain barrier. Expert Opin Drug Deliv 12:1923–1941. https://doi.org/10.1517/17425247.2015.1069815
Barinapa M (1995) Researchers broaden the attack on Parkinson's disease. Science 267:455–456. https://doi.org/10.1126/science.7824944
Bjugstad KB, Teng YD, Redmond DE Jr, Elsworth JD, Roth RH, Cornelius SK, Snyder EY, Sladek JR Jr (2008) Human neural stem cells migrate along the nigrostriatal pathway in a primate model of Parkinson's disease. Exp Neurol 211:362–369. https://doi.org/10.1016/j.expneurol.2008.01.025
Blackburn JK, Curry DW, Thomsen AN, Roth RH, Elsworth JD (2020) Pioglitazone activates paraoxonase-2 in the brain: a novel neuroprotective mechanism. Exp Neurol 327:113234. https://doi.org/10.1016/j.expneurol.2020.113234
Brakedal B, Flones I, Reiter SF, Torkildsen O, Dolle C, Assmus J, Haugarvoll K, Tzoulis C (2017) Glitazone use associated with reduced risk of Parkinson's disease. Mov Disord 32:1594–1599. https://doi.org/10.1002/mds.27128
Bronstein JM, Tagliati M, Alterman RL, Lozano AM, Volkmann J, Stefani A, Horak FB, Okun MS, Foote KD, Krack P, Pahwa R, Henderson JM, Hariz MI, Bakay RA, Rezai A, Marks WJ Jr, Moro E, Vitek JL, Weaver FM, Gross RE, DeLong MR (2011) Deep brain stimulation for Parkinson disease: an expert consensus and review of key issues. Arch Neurol 68:165. https://doi.org/10.1001/archneurol.2010.260
Bullich C, Keshavarzian A, Garssen J, Kraneveld A, Perez-Pardo P (2019) Gut vibes in Parkinson's disease: the microbiota-gut-brain axis. Mov Disord Clin Pract 6:639–651. https://doi.org/10.1002/mdc3.12840
Cai W, Yang T, Liu H, Han L, Zhang K, Hu X, Zhang X, Yin KJ, Gao Y, Bennett MVL, Leak RK, Chen J (2018) Peroxisome proliferator-activated receptor gamma (PPARgamma): a master gatekeeper in CNS injury and repair. Prog Neurobiol 163–164:27–58. https://doi.org/10.1016/j.pneurobio.2017.10.002
Carney BJ, Shah K (2011) Migration and fate of therapeutic stem cells in different brain disease models. Neuroscience 197:37–47. https://doi.org/10.1016/j.neuroscience.2011.08.063
Cassell K, Shaw K, Stern G (1973) A computerised tracking technique for the assessment of Parkinsonian motor disabilities. Brain 96:815–826. https://doi.org/10.1093/brain/96.4.815
Chen H, Ritz B (2018) The search for environmental causes of parkinson's disease: moving forward. J Parkinsons Dis 8:S9–S17. https://doi.org/10.3233/JPD-181493
Chen Y, Zhu G, Shi L, Liu D, Zhang X, Liu Y, Yuan T, Du T, Zhang J (2019) Establishment of a novel mesial temporal lobe epilepsy rhesus monkey model via intra-hippocampal and intra-amygdala kainic acid injection assisted by neurosurgical robot system. Brain Res Bull 149:32–41. https://doi.org/10.1016/j.brainresbull.2019.04.002
Chiueh CC, Markey SP, Burns RS, Johannessen JN, Pert A, Kopin IJ (1984) Neurochemical and behavioral effects of systemic and intranigral administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the rat. Eur J Pharmacol 100:189–194. https://doi.org/10.1016/0014-2999(84)90221-8
Choi-Lundberg DL, Lin Q, Chang YN, Chiang YL, Hay CM, Mohajeri H, Davidson BL, Bohn MC (1997) Dopaminergic neurons protected from degeneration by GDNF gene therapy. Science 275:838–841. https://doi.org/10.1126/science.275.5301.838
Christine CW, Bankiewicz KS, Van Laar AD, Richardson RM, Ravina B, Kells AP, Boot B, Martin AJ, Nutt J, Thompson ME, Larson PS (2019) Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson's disease. Ann Neurol 85:704–714. https://doi.org/10.1002/ana.25450
Costa LG, de Laat R, Dao K, Pellacani C, Cole TB, Furlong CE (2014) Paraoxonase-2 (PON2) in brain and its potential role in neuroprotection. Neurotoxicology 43:3–9. https://doi.org/10.1016/j.neuro.2013.08.011
Danielyan L, Schafer R, von Ameln-Mayerhofer A, Bernhard F, Verleysdonk S, Buadze M, Lourhmati A, Klopfer T, Schaumann F, Schmid B, Koehle C, Proksch B, Weissert R, Reichardt HM, van den Brandt J, Buniatian GH, Schwab M, Gleiter CH, Frey WH 2nd (2011) Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease. Rejuvenation Res 14:3–16. https://doi.org/10.1089/rej.2010.1130
De Los Angeles A, Hyun I, Latham SR, Elsworth JD, Redmond DE Jr (2019) Human-monkey chimeras for modeling human disease: opportunities and challenges. Methods Mol Biol 2005:221–231. https://doi.org/10.1007/978-1-4939-9524-0_15
Desikan RS, Schork AJ, Wang Y, Witoelar A, Sharma M, McEvoy LK, Holland D, Brewer JB, Chen CH, Thompson WK, Harold D, Williams J, Owen MJ, O'Donovan MC, Pericak-Vance MA, Mayeux R, Haines JL, Farrer LA, Schellenberg GD, Heutink P, Singleton AB, Brice A, Wood NW, Hardy J, Martinez M, Choi SH, DeStefano A, Ikram MA, Bis JC, Smith A, Fitzpatrick AL, Launer L, van Duijn C, Seshadri S, Ulstein ID, Aarsland D, Fladby T, Djurovic S, Hyman BT, Snaedal J, Stefansson H, Stefansson K, Gasser T, Andreassen OA, Dale AM, Adni AGC, Investigators I (2015) Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus. Mol Psychiatry 20:1588–1595. https://doi.org/10.1038/mp.2015.6
Devarajan A, Bourquard N, Hama S, Navab M, Grijalva VR, Morvardi S, Clarke CF, Vergnes L, Reue K, Teiber JF, Reddy ST (2011) Paraoxonase 2 deficiency alters mitochondrial function and exacerbates the development of atherosclerosis. Antioxid Redox Signal 14:341–351. https://doi.org/10.1089/ars.2010.3430
Duda J, Potschke C, Liss B (2016) Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease. J Neurochem 139(Suppl 1):156–178. https://doi.org/10.1111/jnc.13572
Elsworth JD, Glover V, Reynolds GP, Sandler M, Lees AJ, Phuapradit P, Shaw KM, Stern GM, Kumar P (1978) Deprenyl administration in man: a selective monoamine oxidase B inhibitor without the 'cheese effect'. Psychopharmacology 57:33–38. https://doi.org/10.1007/bf00426954
Faggiani E, Benazzouz A (2017) Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: from history to the interaction with the monoaminergic systems. Prog Neurobiol 151:139–156. https://doi.org/10.1016/j.pneurobio.2016.07.003
Frankel JP, Hughes A, Lees AJ, Stern GM (1990) Marijuana for parkinsonian tremor. J Neurol Neurosurg Psychiatry 53:436. https://doi.org/10.1136/jnnp.53.5.436
Garrick JM, Dao K, de Laat R, Elsworth J, Cole TB, Marsillach J, Furlong CE, Costa LG (2016) Developmental expression of paraoxonase 2. Chem Biol Interact 259:168–174. https://doi.org/10.1016/j.cbi.2016.04.001
Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, Kotzbauer PT, Trojanowski JQ, Lee VM (2003) Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 300:636–640. https://doi.org/10.1126/science.1082324
Grenier K, Kao J, Diamandis P (2020) Three-dimensional modeling of human neurodegeneration: brain organoids coming of age. Mol Psychiatry 25:254–274. https://doi.org/10.1038/s41380-019-0500-7
Herrero MT, Hirsch EC, Kastner A, Ruberg M, Luquin MR, Laguna J, Javoy-Agid F, Obeso JA, Agid Y (1993) Does neuromelanin contribute to the vulnerability of catecholaminergic neurons in monkeys intoxicated with MPTP? Neuroscience 56:499–511. https://doi.org/10.1016/0306-4522(93)90349-k
Hunter KR, Stern GM, Laurence DR, Armitage P (1970) Combined treatment of parkinsonism with l-dopa and amantadine. Lancet 2:566. https://doi.org/10.1016/s0140-6736(70)91365-6
Investigators NETiPDF-Z (2015) Pioglitazone in early Parkinson's disease: a phase 2, multicentre, double-blind, randomised trial. Lancet Neurol 14:795–803. https://doi.org/10.1016/S1474-4422(15)00144-1
Jellinger KA (2011) Interaction between alpha-synuclein and other proteins in neurodegenerative disorders. Sci World J 11:1893–1907. https://doi.org/10.1100/2011/371893
Kaplitt MG (2019) Gene-targeting approaches for movement disorders: recent advances. Curr Opin Neurol 32:566–570. https://doi.org/10.1097/WCO.0000000000000719
Kirik D, Cederfjall E, Halliday G, Petersen A (2017) Gene therapy for Parkinson's disease: disease modification by GDNF family of ligands. Neurobiol Dis 97:179–188. https://doi.org/10.1016/j.nbd.2016.09.008
Kleedorfer B, Turjanski N, Ryan R, Lees AJ, Milroy C, Stern GM (1991) Intranasal apomorphine in Parkinson's disease. Neurology 41:761–762. https://doi.org/10.1212/wnl.41.5.761-a
Lees AJ, Shaw KM, Kohout LJ, Stern GM, Elsworth JD, Sandler M, Youdim MB (1977) Deprenyl in Parkinson's disease. Lancet 2:791–795. https://doi.org/10.1016/s0140-6736(77)90725-5
Lees AJ, Shaw KM, Stern GM (1978) Baclofen in Parkinson's disease. J Neurol Neurosurg Psychiatry 41:707–708. https://doi.org/10.1136/jnnp.41.8.707
Li YI, Wong G, Humphrey J, Raj T (2019) Prioritizing Parkinson's disease genes using population-scale transcriptomic data. Nat Commun 10:994. https://doi.org/10.1038/s41467-019-08912-9
Liang CL, Nelson O, Yazdani U, Pasbakhsh P, German DC (2004) Inverse relationship between the contents of neuromelanin pigment and the vesicular monoamine transporter-2: human midbrain dopamine neurons. J Comp Neurol 473:97–106. https://doi.org/10.1002/cne.20098
Lindholm D, Eriksson O, Makela J, Belluardo N, Korhonen L (2012) PGC-1alpha: a master gene that is hard to master. Cell Mol Life Sci 69:2465–2468. https://doi.org/10.1007/s00018-012-1043-0
Lindvall O (2015) Treatment of Parkinson's disease using cell transplantation. Philos Trans R Soc Lond B Biol Sci 370:20140370. https://doi.org/10.1098/rstb.2014.0370
Lu CH, Yang CY, Li CY, Hsieh CY, Ou HT (2018) Lower risk of dementia with pioglitazone, compared with other second-line treatments, in metformin-based dual therapy: a population-based longitudinal study. Diabetologia 61:562–573. https://doi.org/10.1007/s00125-017-4499-5
Machado MMF, Bassani TB, Coppola-Segovia V, Moura ELR, Zanata SM, Andreatini R, Vital M (2019) PPAR-gamma agonist pioglitazone reduces microglial proliferation and NF-kappaB activation in the substantia nigra in the 6-hydroxydopamine model of Parkinson's disease. Pharmacol Rep 71:556–564. https://doi.org/10.1016/j.pharep.2018.11.005
Marotta N, Kim S, Krainc D (2020) Organoid and pluripotent stem cells in Parkinson's disease modeling: an expert view on their value to drug discovery. Expert Opin Drug Discov. https://doi.org/10.1080/17460441.2020.1703671
Marsden CD (1983) Neuromelanin and Parkinson's disease. J Neural Transm Suppl 19:121–141
McCaul JA, Stern GM (1974) Letter: Lithium in Parkinson's disease. Lancet 1:1117. https://doi.org/10.1016/s0140-6736(74)90602-3
McCaul JA, Cassell KJ, Stern GM (1974) Letter: intravenous thyrotrophin-releasing hormone in Parkinson's disease. Lancet 1:735. https://doi.org/10.1016/s0140-6736(74)92939-0
Morizane A, Kikuchi T, Hayashi T, Mizuma H, Takara S, Doi H, Mawatari A, Glasser MF, Shiina T, Ishigaki H, Itoh Y, Okita K, Yamasaki E, Doi D, Onoe H, Ogasawara K, Yamanaka S, Takahashi J (2017) MHC matching improves engraftment of iPSC-derived neurons in non-human primates. Nat Commun 8:385. https://doi.org/10.1038/s41467-017-00926-5
Morrow BA, Roth RH, Redmond DE, Elsworth JD (2011) Impact of methamphetamine on dopamine neurons in primates is dependent on age: implications for development of Parkinson's disease. Neuroscience 189:277–285. https://doi.org/10.1016/j.neuroscience.2011.05.046
Morrow BA, Roth RH, Redmond DE Jr, Diano S, Elsworth JD (2012) Susceptibility to a parkinsonian toxin varies during primate development. Exp Neurol 235:273–281. https://doi.org/10.1016/j.expneurol.2012.02.005
Pacelli C, Giguere N, Bourque MJ, Levesque M, Slack RS, Trudeau LE (2015) Elevated mitochondrial bioenergetics and axonal arborization size are key contributors to the vulnerability of dopamine neurons. Curr Biol 25:2349–2360. https://doi.org/10.1016/j.cub.2015.07.050
Parmar M (2018) Towards stem cell based therapies for Parkinson's disease. Development. https://doi.org/10.1242/dev.156117
Parsanejad M, Bourquard N, Qu D, Zhang Y, Huang E, Rousseaux MW, Aleyasin H, Irrcher I, Callaghan S, Vaillant DC, Kim RH, Slack RS, Mak TW, Reddy ST, Figeys D, Park DS (2014) DJ-1 interacts with and regulates paraoxonase-2, an enzyme critical for neuronal survival in response to oxidative stress. PLoS ONE 9:e106601. https://doi.org/10.1371/journal.pone.0106601
Pissadaki EK, Bolam JP (2013) The energy cost of action potential propagation in dopamine neurons: clues to susceptibility in Parkinson's disease. Front Comput Neurosci 7:13. https://doi.org/10.3389/fncom.2013.00013
Pozo Devoto VM, Falzone TL (2017) Mitochondrial dynamics in Parkinson's disease: a role for alpha-synuclein? Dis Model Mech 10:1075–1087. https://doi.org/10.1242/dmm.026294
Riederer P, Berg D, Casadei N, Cheng F, Classen J, Dresel C, Jost W, Kruger R, Muller T, Reichmann H, Riess O, Storch A, Strobel S, van Eimeren T, Volker HU, Winkler J, Winklhofer KF, Wullner U, Zunke F, Monoranu CM (2019) alpha-Synuclein in Parkinson's disease: causal or bystander? J Neural Transm (Vienna) 126:815–840. https://doi.org/10.1007/s00702-019-02025-9
Sandler M, Corne SJ, Stephens R, Shaw DM, Hunter DR, Stern GM (1972) Metatyrosine in the treatment of parkinsonism. Lancet 2:605. https://doi.org/10.1016/s0140-6736(72)92006-5
Scaduto CM (2016) Methods for creating transgenic primates. Lab Anim (NY) 45:291–292. https://doi.org/10.1038/laban.1068
Sharma A, Osato N, Liu H, Asthana S, Dakal TC, Ambrosini G, Bucher P, Schmitt I, Wullner U (2019) Common genetic variants associated with Parkinson's disease display widespread signature of epigenetic plasticity. Sci Rep 9:18464. https://doi.org/10.1038/s41598-019-54865-w
Shaw KM, Stern GM, Sandler M (1973) Melatonin and parkinsonism. Lancet 1:271. https://doi.org/10.1016/s0140-6736(73)90118-9
Stefanis L (2012) alpha-Synuclein in Parkinson's disease. Cold Spring Harb Perspect Med 2:a009399. https://doi.org/10.1101/cshperspect.a009399
Stern G (1966) The effects of lesions in the substantia nigra. Brain 89:449–478. https://doi.org/10.1093/brain/89.3.449
Stern G (1969) Parkinsonism. Br Med J 4:541–542. https://doi.org/10.1136/bmj.4.5682.541
Stern GM (1987) Vitamin E and Parkinson's disease. Lancet 1:508. https://doi.org/10.1016/s0140-6736(87)92120-9
Stern G (2012a) Genetics and the neurodegenerations: musings of a gadfly. J Parkinsons Dis 2:1–5. https://doi.org/10.3233/JPD-2012-11065
Stern G (2012b) The horse that wouldn't run. Pract Neurol 12:63–67. https://doi.org/10.1136/practneurol-2011-000113
Stibe CM, Lees AJ, Kempster PA, Stern GM (1988) Subcutaneous apomorphine in Parkinsonian on-off oscillations. Lancet 1:403–406. https://doi.org/10.1016/s0140-6736(88)91193-2
Surmeier DJ, Schumacker PT, Guzman JD, Ilijic E, Yang B, Zampese E (2017) Calcium and Parkinson's disease. Biochem Biophys Res Commun 483:1013–1019. https://doi.org/10.1016/j.bbrc.2016.08.168
Swanson CR, Joers V, Bondarenko V, Brunner K, Simmons HA, Ziegler TE, Kemnitz JW, Johnson JA, Emborg ME (2011) The PPAR-gamma agonist pioglitazone modulates inflammation and induces neuroprotection in Parkinsonian monkeys. J Neuroinflamm 8:91. https://doi.org/10.1186/1742-2094-8-91
Tseng CH (2018) Pioglitazone reduces dementia risk in patients with type 2 diabetes mellitus: a retrospective cohort analysis. J Clin Med. https://doi.org/10.3390/jcm7100306
Ur Rasheed MS, Mishra AK, Singh MP (2017) Cytochrome P450 2D6 and Parkinson's disease: polymorphism metabolic role, risk and protection. Neurochem Res 42:3353–3361. https://doi.org/10.1007/s11064-017-2384-8
van Heesbeen HJ, Smidt MP (2019) Entanglement of genetics and epigenetics in Parkinson's disease. Front Neurosci 13:277. https://doi.org/10.3389/fnins.2019.00277
Vila M (2019) Neuromelanin, aging, and neuronal vulnerability in Parkinson's disease. Mov Disord 34:1440–1451. https://doi.org/10.1002/mds.27776
Wang D, Li S, Gessler DJ, Xie J, Zhong L, Li J, Tran K, Van Vliet K, Ren L, Su Q, He R, Goetzmann JE, Flotte TR, Agbandje-McKenna M, Gao G (2018) A rationally engineered capsid variant of AAV9 for systemic CNS-directed and peripheral tissue-detargeted gene delivery in neonates. Mol Ther Methods Clin Dev 9:234–246. https://doi.org/10.1016/j.omtm.2018.03.004
Ward C, Stern GM, Pratt RT, McKenna P (1980) Electroconvulsive therapy in Parkinsonian patients with the "on-off" syndrome. J Neural Transm 49:133–135. https://doi.org/10.1007/bf01249195
Wolf DP, Morey R, Kang E, Ma H, Hayama T, Laurent LC, Mitalipov S (2017) Concise review: embryonic stem cells derived by somatic cell nuclear transfer: a horse in the race? Stem Cells 35:26–34. https://doi.org/10.1002/stem.2496
Wu HF, Kao LT, Shih JH, Kao HH, Chou YC, Li IH, Kao S (2018) Pioglitazone use and Parkinson's disease: a retrospective cohort study in Taiwan. BMJ Open 8:e023302. https://doi.org/10.1136/bmjopen-2018-023302
Youle RJ, van der Bliek AM (2012) Mitochondrial fission, fusion, and stress. Science 337:1062–1065. https://doi.org/10.1126/science.1219855
Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR (2004) Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 5:863–873. https://doi.org/10.1038/nrn1537
Zhang PL, Chen Y, Zhang CH, Wang YX, Fernandez-Funez P (2018) Genetics of Parkinson's disease and related disorders. J Med Genet 55:73–80. https://doi.org/10.1136/jmedgenet-2017-105047
Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML, Eklund AC, Zhang-James Y, Kim PD, Hauser MA, Grunblatt E, Moran LB, Mandel SA, Riederer P, Miller RM, Federoff HJ, Wullner U, Papapetropoulos S, Youdim MB, Cantuti-Castelvetri I, Young AB, Vance JM, Davis RL, Hedreen JC, Adler CH, Beach TG, Graeber MB, Middleton FA, Rochet JC, Scherzer CR, Global PDGEC (2010) PGC-1alpha, a potential therapeutic target for early intervention in Parkinson's disease. Sci Transl Med 2:52ra73. https://doi.org/10.1126/scitranslmed.3001059
Zhou J, Bradford HF, Stern GM (1997) Influence of BDNF on the expression of the dopaminergic phenotype of tissue used for brain transplants. Brain Res Dev Brain Res 100:43–51. https://doi.org/10.1016/s0165-3806(97)00019-9
Acknowledgements
Supported by AG048918 to JDE.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The author has no financial disclosure to make or have any conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Elsworth, J.D. Parkinson’s disease treatment: past, present, and future. J Neural Transm 127, 785–791 (2020). https://doi.org/10.1007/s00702-020-02167-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-020-02167-1