Abstract
Existing therapeutic strategies for managing Parkinson disease (PD), which focus on addressing the loss of dopamine and dopaminergic function linked with degeneration of dopaminergic neurons, are limited by side effects and lack of long-term efficacy. In recent decades, research into PD pathophysiology and pharmacology has focused on understanding and tackling the neurodegenerative processes and symptomology of PD. In this Review, we discuss the challenges associated with the development of novel therapies for PD, highlighting emerging agents that aim to target cell death, as well as new targets offering a symptomatic approach to managing features and progression of the disease.
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Change history
12 October 2018
In the original version of Figure 3, a dopamine D2 receptor had been positioned incorrectly and has now been moved to the correct presynaptic position on the dopaminergic neurons projecting to the basal ganglia motor circuit. In addition, the two Figure 2 citations that appeared on page 14 were incorrect and have now been changed to Figure 3.
References
Parkinson, J. An essay on the shaking palsy. 1817. J. Neuropsychiatry Clin. Neurosci. 14, 223–236 (2002). This essay is the first clear clinical description of the shaking palsy, or paralysis agitans, that we now refer to as PD.
Donaldson, I. M. James Parkinson's essay on the shaking palsy. J. R. Coll. Physicians Edinb. 45, 84–86 (2015).
Birkmayer, W. & Hornykiewicz, O. The L-dihydroxyphenylalanine (L-DOPA) effect in Parkinson's syndrome in man: on the pathogenesis and treatment of Parkinson akinesis [German]. Arch. Psychiatr. Nervenkr. Z. Gesamte Neurol. Psychiatr. 203, 560–574 (1962).
Birkmayer, W. & Hornykiewicz, O. Additional experimental studies on L-DOPA in Parkinson's syndrome and reserpine parkinsonism [German]. Arch. Psychiatr. Nervenkr. 206, 367–381 (1964).
Zeng, X. S., Geng, W. S., Jia, J. J., Chen, L. & Zhang, P. P. Cellular and molecular basis of neurodegeneration in Parkinson disease. Front. Aging Neurosci. 10, 109 (2018).
Poewe, W. et al. Parkinson disease. Nat. Rev. Dis. Primers 3, 17013 (2017). This paper provides a comprehensive review on our current understanding of the underlying pathology and molecular pathogenesis of PD.
Obeso, J. A. et al. Past, present, and future of Parkinson's disease: a special essay on the 200th anniversary of the shaking palsy. Mov. Disord. 32, 1264–1310 (2017). Prepared to commemorate the bicentenary of PD, this extensive review provides a historical state-of-the-art account of what has been achieved, the current situation and how to progress towards identifying treatments.
Michel, P. P., Hirsch, E. C. & Hunot, S. Understanding dopaminergic cell death pathways in Parkinson disease. Neuron 90, 675–691 (2016). This paper provides a comprehensive review of the mechanisms that are suspected to participate in dopaminergic cell death in PD.
Fink, A. L. The aggregation and fibrillation of alpha-synuclein. Acc. Chem. Res. 39, 628–634 (2006).
Lashuel, H. A., Overk, C. R., Oueslati, A. & Masliah, E. The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nat. Rev. Neurosci. 14, 38–48 (2013). This review provides an overview of the current knowledge regarding the role of α-synuclein states in regulating its function under physiological and pathophysiological conditions.
Kaushik, S. & Cuervo, A. M. Proteostasis and aging. Nat. Med. 21, 1406–1415 (2015).
Xilouri, M., Brekk, O. R. & Stefanis, L. α-Synuclein and protein degradation systems: a reciprocal relationship. Mol. Neurobiol. 47, 537–551 (2013).
Bastide, M. F. et al. Pathophysiology of L-DOPA-induced motor and non-motor complications in Parkinson's disease. Prog. Neurobiol. 132, 96–168 (2015).
Moore, T. J., Glenmullen, J. & Mattison, D. R. Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs. JAMA Intern. Med. 174, 1930–1933 (2014).
Schrag, A., Jahanshahi, M. & Quinn, N. What contributes to quality of life in patients with Parkinson's disease? J. Neurol. Neurosurg. Psychiatry 69, 308–312 (2000).
Izurieta-Sanchez, P., Sarre, S., Ebinger, G. & Michotte, Y. Effect of trihexyphenidyl, a non-selective antimuscarinic drug, on decarboxylation of L-DOPA in hemi-Parkinson rats. Eur. J. Pharmacol. 353, 33–42 (1998).
Schwab, R. S., England, A. C. Jr., Poskanzer, D. C. & Young, R. R. Amantadine in the treatment of Parkinson's disease. JAMA 208, 1168–1170 (1969).
Athauda, D. & Foltynie, T. The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson's disease: mechanisms of action. Drug Discov. Today 21, 802–818 (2016).
Kieburtz, K. & Olanow, C. W. Advances in clinical trials for movement disorders. Mov. Disord. 30, 1580–1587 (2015).
McGhee, D. J., Ritchie, C. W., Zajicek, J. P. & Counsell, C. E. A review of clinical trial designs used to detect a disease-modifying effect of drug therapy in Alzheimer's disease and Parkinson's disease. BMC Neurol. 16, 92 (2016).
Bartus, R. T., Weinberg, M. S. & Samulski, R. J. Parkinson's disease gene therapy: success by design meets failure by efficacy. Mol. Ther. 22, 487–497 (2014).
Zeiss, C. J., Allore, H. G. & Beck, A. P. Established patterns of animal study design undermine translation of disease-modifying therapies for Parkinson's disease. PLOS ONE 12, e0171790 (2017).
Magen, I. & Chesselet, M. F. Genetic mouse models of Parkinson's disease: the state of the art. Prog. Brain Res. 184, 53–87 (2010).
Bezard, E., Yue, Z., Kirik, D. & Spillantini, M. G. Animal models of Parkinson's disease: limits and relevance to neuroprotection studies. Mov. Disord. 28, 61–70 (2013).
Dehay, B. & Fernagut, P. O. Alpha-synuclein-based models of Parkinson's disease. Rev. Neurol. 172, 371–378 (2016).
Ko, W. K. D. & Bezard, E. Experimental animal models of Parkinson's disease: a transition from assessing symptomatology to alpha-synuclein targeted disease modification. Exp. Neurol. 298 (Suppl. B), 172–179 (2017). This article provides a review on the current animal models of PD and describes the transition from well-established animal models of PD symptomatology to models being developed to assess neuroprotective strategies.
Bourdenx, M. et al. Protein aggregation and neurodegeneration in prototypical neurodegenerative diseases: examples of amyloidopathies, tauopathies and synucleinopathies. Prog. Neurobiol. 155, 171–193 (2017).
Bourdenx, M. et al. Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by alpha-synuclein overexpression. Acta Neuropathol. Commun. 3, 46 (2015).
Koprich, J. B., Johnston, T. H., Reyes, G., Omana, V. & Brotchie, J. M. Towards a non-human primate model of alpha-synucleinopathy for development of therapeutics for Parkinson's disease: optimization of AAV1/2 delivery parameters to drive sustained expression of alpha synuclein and dopaminergic degeneration in macaque. PLOS ONE 11, e0167235 (2016).
European Agency for Evaluation of Medicinal Products. Guideline on clinical investigation of medicinal products in the treatment of Parkinson's disease. Eur. Neuropsychophamarcol. 9, 443–449 (2012).
Oertel, W. H. Recent advances in treating Parkinson's disease. F1000Res 6, 260 (2017).
Sauerbier, A., Qamar, M. A., Rajah, T. & Chaudhuri, K. R. New concepts in the pathogenesis and presentation of Parkinson's disease. Clin. Med. 16, 365–370 (2016).
Andersen, A. D., Binzer, M., Stenager, E. & Gramsbergen, J. B. Cerebrospinal fluid biomarkers for Parkinson's disease - a systematic review. Acta Neurol. Scand. 135, 34–56 (2017).
Kalia, L. V. & Lang, A. E. Parkinson's disease. Lancet 386, 896–912 (2015).
Saracchi, E., Fermi, S. & Brighina, L. Emerging candidate biomarkers for Parkinson's disease: a review. Aging Dis. 5, 27–34 (2014).
Burciu, R. G. et al. Progression marker of Parkinson's disease: a 4-year multi-site imaging study. Brain 140, 2183–2192 (2017). Using MRI data from the PPMI study, results presented in this article support the potential of free water in the posterior substantia nigra as an imaging biomarker for PD progression.
Fereshtehnejad, S. M., Zeighami, Y., Dagher, A. & Postuma, R. B. Clinical criteria for subtyping Parkinson's disease: biomarkers and longitudinal progression. Brain 140, 1959–1976 (2017).
Schrag, A., Siddiqui, U. F., Anastasiou, Z., Weintraub, D. & Schott, J. M. Clinical variables and biomarkers in prediction of cognitive impairment in patients with newly diagnosed Parkinson's disease: a cohort study. Lancet Neurol. 16, 66–75 (2017).
Athauda, D. et al. Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial. Lancet 390, 1664–1675 (2017).
Aviles-Olmos, I. et al. Motor and cognitive advantages persist 12 months after exenatide exposure in Parkinson's disease. J. Parkinsons Dis. 4, 337–344 (2014).
Hauser, R. A. et al. Time course of loss of clinical benefit following withdrawal of levodopa/carbidopa and bromocriptine in early Parkinson's disease. Mov. Disord. 15, 485–489 (2000).
Hauser, R. A. & Holford, N. H. Quantitative description of loss of clinical benefit following withdrawal of levodopa-carbidopa and bromocriptine in early Parkinson's disease. Mov. Disord. 17, 961–968 (2002).
Hauser, R. A. & Zesiewicz, T. A. Clinical trials aimed at detecting neuroprotection in Parkinson's disease. Neurology 66, S58–68 (2006).
Foltynie, T., Brayne, C. & Barker, R. A. The heterogeneity of idiopathic Parkinson's disease. J. Neurol. 249, 138–145 (2002).
Sieber, B. A. et al. Prioritized research recommendations from the National Institute of Neurological Disorders and Stroke Parkinson's Disease 2014 conference. Ann. Neurol. 76, 469–472 (2014).
Athauda, D. & Foltynie, T. Challenges in detecting disease modification in Parkinson's disease clinical trials. Parkinsonism Relat. Disord. 32, 1–11 (2016).
Lang, A. E. & Espay, A. J. Disease modification in Parkinson's disease: current approaches, challenges, and future considerations. Mov. Disord. 33, 660–677 (2018).
Jenner, P. & Olanow, C. W. Oxidative stress and the pathogenesis of Parkinson's disease. Neurology 47, S161–S170 (1996).
Bose, A. & Beal, M. F. Mitochondrial dysfunction in Parkinson's disease. J. Neurochem. 139 (Suppl. 1), 216–231 (2016). This review provides an overview of the mechanisms that can cause mitochondrial dysfunction in PD.
Cristovao, A. C. et al. NADPH oxidase 1 mediates alpha-synucleinopathy in Parkinson's disease. J. Neurosci. 32, 14465–14477 (2012).
Ko, H. S. et al. Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function. Proc. Natl Acad. Sci. USA 107, 16691–16696 (2010).
Imam, S. Z. et al. Novel regulation of parkin function through c-Abl-mediated tyrosine phosphorylation: implications for Parkinson's disease. J. Neurosci. 31, 157–163 (2011).
Zhao, J., Yu, S., Zheng, Y., Yang, H. & Zhang, J. Oxidative modification and its implications for the neurodegeneration of Parkinson's disease. Mol. Neurobiol. 54, 1404–1418 (2017).
Cacabelos, R. Parkinson's disease: from pathogenesis to pharmacogenomics. Int. J. Mol. Sci. 18, 551 (2017).
Hauser, D. N. & Hastings, T. G. Mitochondrial dysfunction and oxidative stress in Parkinson's disease and monogenic parkinsonism. Neurobiol. Dis. 51, 35–42 (2013).
Parkinson Study Group QE3 Investigators. A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit. JAMA Neurol. 71, 543–552 (2014).
Yang, L. et al. Combination therapy with coenzyme Q10 and creatine produces additive neuroprotective effects in models of Parkinson's and Huntington's diseases. J. Neurochem. 109, 1427–1439 (2009).
Spindler, M., Beal, M. F. & Henchcliffe, C. Coenzyme Q10 effects in neurodegenerative disease. Neuropsychiatr. Dis. Treat. 5, 597–610 (2009).
Cleren, C. et al. Therapeutic effects of coenzyme Q10 (CoQ10) and reduced CoQ10 in the MPTP model of Parkinsonism. J. Neurochem. 104, 1613–1621 (2008).
Agarwal, S., Yadav, A. & Chaturvedi, R. K. Peroxisome proliferator-activated receptors (PPARs) as therapeutic target in neurodegenerative disorders. Biochem. Biophys. Res. Commun. 483, 1166–1177 (2017).
Swanson, C. R. et al. The PPAR-gamma agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeys. J. Neuroinflamm. 8, 91 (2011).
NINDS Exploratory Trials in Parkinson Disease (NET-PD) FS-ZONE Investigators. Pioglitazone in early Parkinson's disease: a phase 2, multicentre, double-blind, randomised trial. Lancet Neurol. 14, 795–803 (2015).
Simon, D. K. et al. Peripheral biomarkers of Parkinson's disease progression and pioglitazone effects. J. Parkinsons Dis. 5, 731–736 (2015).
Blits, B. & Petry, H. Perspective on the road toward gene therapy for Parkinson's disease. Front. Neuroanat. 10, 128 (2016).
Gash, D. M. et al. Functional recovery in parkinsonian monkeys treated with GDNF. Nature 380, 252–255 (1996).
Emborg, M. E. et al. Response of aged parkinsonian monkeys to in vivo gene transfer of GDNF. Neurobiol. Dis. 36, 303–311 (2009).
Kordower, J. H. et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science 290, 767–773 (2000).
Nutt, J. G. et al. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 60, 69–73 (2003).
Lang, A. E. et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann. Neurol. 59, 459–466 (2006).
Warren Olanow, C. et al. Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: a double-blind, randomized, controlled trial. Ann. Neurol. 78, 248–257 (2015).
Decressac, M. et al. α-Synuclein-induced down-regulation of Nurr1 disrupts GDNF signaling in nigral dopamine neurons. Sci. Transl Med. 4, 163ra156 (2012).
Chung, C. Y., Koprich, J. B., Siddiqi, H. & Isacson, O. Dynamic changes in presynaptic and axonal transport proteins combined with striatal neuroinflammation precede dopaminergic neuronal loss in a rat model of AAV alpha-synucleinopathy. J. Neurosci. 29, 3365–3373 (2009).
Nalls, M. A. et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat. Genet. 46, 989–993 (2014).
West, A. B. Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease. Exp. Neurol. 298, 236–245 (2017).
Sardi, S. P., Cedarbaum, J. M. & Brundin, P. Targeted therapies for Parkinson's disease: from genetics to the clinic. Mov. Disord. 33, 684–696 (2018).
Palfi, S. et al. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial. Lancet 383, 1138–1146 (2014).
Jarraya, B. et al. Dopamine gene therapy for Parkinson's disease in a nonhuman primate without associated dyskinesia. Sci. Transl Med. 1, 2ra4 (2009).
Goetz, C. G. et al. Placebo response in Parkinson's disease: comparisons among 11 trials covering medical and surgical interventions. Mov. Disord. 23, 690–699 (2008).
Stewart, H. J. et al. Optimizing transgene configuration and protein fusions to maximize dopamine production for the gene therapy of Parkinson's disease. Hum. Gene Ther. Clin. Dev. 27, 100–110 (2016).
Axovant Sciences Ltd. Axovant licenses investigational gene therapy for Parkinson's disease from Oxford BioMedica and announces key leadership team addition. Axovant http://investors.axovant.com/node/7551/pdf (2018).
Ciesielska, A. et al. Depletion of AADC activity in caudate nucleus and putamen of Parkinson's disease patients; implications for ongoing AAV2-AADC gene therapy trial. PLOS ONE 12, e0169965 (2017).
San Sebastian, W. et al. Safety and tolerability of MRI-guided infusion of AAV2-hAADC into the mid-brain of non-human primate. Mol. Ther. Methods Clin. Dev. 1, 14049 (2014).
Mittermeyer, G. et al. Long-term evaluation of a phase 1 study of AADC gene therapy for Parkinson's disease. Hum. Gene Ther. 23, 377–381 (2012).
Voyager Therapeutics Inc. Voyager Therapeutics announces positive results from ongoing phase 1b trial of VY-AADC01 for advanced Parkinson's disease. Voyager Therapeutics http://ir.voyagertherapeutics.com/phoenix.zhtml?c=254026&p=irol-newsArticle&ID=2298649 (2017).
Voyager Therapeutics Inc. Voyager Therapeutics announces FDA Regenerative Medicine Advanced Therapy (RMAT) designation granted for VY-AADC for the treatment of Parkinson's disease. Voyager Therapeutics http://ir.voyagertherapeutics.com/phoenix.zhtml?c=254026&p=irol-newsArticle&ID=2355428 (2018).
Dickson, D. W. et al. Neuropathological assessment of Parkinson's disease: refining the diagnostic criteria. Lancet Neurol. 8, 1150–1157 (2009).
Olanow, C. W. & Kordower, J. H. Targeting alpha-synuclein as a therapy for Parkinson's disease: the battle begins. Mov. Disord. 32, 203–207 (2017).
Masliah, E. et al. Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLOS ONE 6, e19338 (2011).
Games, D. et al. Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson's disease-like models. J. Neurosci. 34, 9441–9454 (2014).
Schenk, D. B. et al. First-in-human assessment of PRX002, an anti-alpha-synuclein monoclonal antibody, in healthy volunteers. Mov. Disord. 32, 211–218 (2017).
Jankovic, J. et al. Safety and tolerability of multiple ascending doses of PRX002/RG7935, an anti-α-synuclein monoclonal antibody, in patients with Parkinson disease: a randomized clinical trial. JAMA Neurol. https://doi.org/10.1001/jamaneurol.2018.1487 (2018).
Mandler, M. et al. Next-generation active immunization approach for synucleinopathies: implications for Parkinson's disease clinical trials. Acta Neuropathol. 127, 861–879 (2014).
AFFiRiS. AFFiRiS announces top line results of first-in-human clinical study using AFFITOPE® PD03A, confirming immunogenicity and safety profile in Parkinson's disease patients. Cision PR Newswire https://www.prnewswire.com/news-releases/affiris-announces-top-line-results-of-first-in-human-clinical-study-using-affitope-pd03a-confirming-immunogenicity-and-safety-profile-in-parkinsons-disease-patients-627025511.html (2017).
Poewe, W. et al. in AAT-AD/PD Focus Meeting 2018 (Torino, Italy, 2018).
Brys, M. et al. Randomized, double-blind, placebo-controlled, single ascending dose study of anti-alpha-synuclein antibody BIIB054 in patients with Parkinson's disease (S26.001). Neurology 90 (Suppl. 15), S26.001 (2018).
Weihofen, A. et al. in 13th International Conference on Alzheimer's and Parkinson's Diseases (Vienna, Austria, 2017).
Wagner, J. et al. Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease. Acta Neuropathol. 125, 795–813 (2013).
Szoke, B. et al. in Society for Neuroscience: Neuroscience 2014 (Washington DC, 2014).
Wrasidlo, W. et al. A de novo compound targeting alpha-synuclein improves deficits in models of Parkinson's disease. Brain 139, 3217–3236 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02606682 (2016).
McCormack, A. L. et al. Alpha-synuclein suppression by targeted small interfering RNA in the primate substantia nigra. PLOS ONE 5, e12122 (2010).
US Department of Health and Human Services. New therapy addresses unmet medical need for rare disease. FDA.gov https://www.fda.gov/downloads/forindustry/developingproductsforrarediseasesconditions/designatinghumanitarianusedeviceshuds/ucm597204.pdf (2016).
Finkel, R. S. et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet 388, 3017–3026 (2016).
Finkel, R. S. et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N. Engl. J. Med. 377, 1723–1732 (2017).
Ionis Pharmaceuticals Inc. Ionis Pharmaceuticals licenses IONIS-HTT Rx to partner following successful phase 1/2a study in patients with Huntington's disease. Ionis Pharmaceuticals http://ir.ionispharma.com/node/23031/pdf (2017).
Wild, E. J. & Tabrizi, S. J. Therapies targeting DNA and RNA in Huntington's disease. Lancet Neurol. 16, 837–847 (2017).
Gorenberg, E. L. & Chandra, S. S. The role of co-chaperones in synaptic proteostasis and neurodegenerative disease. Front. Neurosci. 11, 248 (2017).
Moors, T. E. et al. Therapeutic potential of autophagy-enhancing agents in Parkinson's disease. Mol. Neurodegener. 12, 11 (2017).
Sian, J. et al. Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basal ganglia. Ann. Neurol. 36, 348–355 (1994).
Witschi, A., Reddy, S., Stofer, B. & Lauterburg, B. H. The systemic availability of oral glutathione. Eur. J. Clin. Pharmacol. 43, 667–669 (1992).
Hauser, R. A., Lyons, K. E., McClain, T., Carter, S. & Perlmutter, D. Randomized, double-blind, pilot evaluation of intravenous glutathione in Parkinson's disease. Mov. Disord. 24, 979–983 (2009).
Mischley, L. K., Lau, R. C., Shankland, E. G., Wilbur, T. K. & Padowski, J. M. Phase IIb study of intranasal glutathione in Parkinson's disease. J. Parkinsons Dis. 7, 289–299 (2017).
Mischley, L. K. et al. Central nervous system uptake of intranasal glutathione in Parkinson's disease. NPJ Parkinsons Dis. 2, 16002 (2016).
O'Regan, G., deSouza, R. M., Balestrino, R. & Schapira, A. H. Glucocerebrosidase mutations in Parkinson disease. J. Parkinsons Dis. 7, 411–422 (2017).
Beavan, M. S. & Schapira, A. H. Glucocerebrosidase mutations and the pathogenesis of Parkinson disease. Ann. Med. 45, 511–521 (2013).
Migdalska-Richards, A. & Schapira, A. H. The relationship between glucocerebrosidase mutations and Parkinson disease. J. Neurochem. 139 (Suppl. 1), 77–90 (2016).
Sardi, S. P. et al. Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies. Proc. Natl Acad. Sci. USA 110, 3537–3542 (2013).
Zunke, F. et al. Reversible conformational conversion of alpha-synuclein into toxic assemblies by glucosylceramide. Neuron 97, 92–107 (2017).
Kim, S. et al. GBA1 deficiency negatively affects physiological alpha-synuclein tetramers and related multimers. Proc. Natl Acad. Sci. USA 115, 798–803 (2018).
Migdalska-Richards, A., Daly, L., Bezard, E. & Schapira, A. H. Ambroxol effects in glucocerebrosidase and alpha-synuclein transgenic mice. Ann. Neurol. 80, 766–775 (2016).
Schapira, A. H., Chiasserini, D., Beccari, T. & Parnetti, L. Glucocerebrosidase in Parkinson's disease: insights into pathogenesis and prospects for treatment. Mov. Disord. 31, 830–835 (2016).
Ambrosi, G. et al. Ambroxol-induced rescue of defective glucocerebrosidase is associated with increased LIMP-2 and saposin C levels in GBA1 mutant Parkinson's disease cells. Neurobiol. Dis. 82, 235–242 (2015).
Allergan plc. Allergan enters Parkinson's disease through option arrangement with Lysosomal Therapeutics Inc. (LTI) for its potential first-in-class breakthrough compounds. Cision PR Newswire https://www.prnewswire.com/news-releases/allergan-enters-parkinsons-disease-through-option-arrangement-with-lysosomal-therapeutics-inc-lti-for-its-potential-first-in-class-breakthrough-compounds-300387519.html (2017).
Marshall, J. et al. CNS-accessible inhibitor of glucosylceramide synthase for substrate reduction therapy of neuronopathic Gaucher disease. Mol. Ther. 24, 1019–1029 (2016).
Sanofi Genzyme. Sanofi initiates phase 2 clinical trial to evaluate therapy for genetic form of Parkinson's disease. Sanofi Genzyme https://news.genzyme.com/press-release/sanofi-initiates-phase-2-clinical-trial-evaluate-therapy-genetic-form-parkinsons-disea (2017).
Amicus Therapeutics. Amicus Therapeutics announces preliminary results of phase 2 study with Plicera(TM) for Gaucher disease. Amicus Therapeutics http://ir.amicusrx.com/static-files/35813147-7c02-4311-b770-9279142ee4da (2009).
Belaidi, A. A. & Bush, A. I. Iron neurochemistry in Alzheimer's disease and Parkinson's disease: targets for therapeutics. J. Neurochem. 139 (Suppl. 1), 179–197 (2016).
Kaur, D. et al. Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease. Neuron 37, 899–909 (2003).
Weinreb, O., Mandel, S., Youdim, M. B. & Amit, T. Targeting dysregulation of brain iron homeostasis in Parkinson's disease by iron chelators. Free Radic. Biol. Med. 62, 52–64 (2013).
Devos, D. et al. Targeting chelatable iron as a therapeutic modality in Parkinson's disease. Antioxid. Redox Signal. 21, 195–210 (2014).
Athauda, D. & Foltynie, T. Insulin resistance and Parkinson's disease: a new target for disease modification? Prog. Neurobiol. 145–146, 98–120 (2016). This article reviews the evidence suggesting that PD and insulin resistance share common underlying pathological mechanisms.
Dunn, L. et al. Dysregulation of glucose metabolism is an early event in sporadic Parkinson's disease. Neurobiol. Aging 35, 1111–1115 (2014).
Aksoy, D. et al. Neuroprotective effects of eexenatide in a rotenone-induced rat model of Parkinson's disease. Am. J. Med. Sci. 354, 319–324 (2017).
Athauda, D., Wyse, R., Brundin, P. & Foltynie, T. Is exenatide a treatment for Parkinson's disease? J. Parkinsons Dis. 7, 451–458 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03456687 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02953665 (2016).
Atashrazm, F. & Dzamko, N. LRRK2 inhibitors and their potential in the treatment of Parkinson's disease: current perspectives. Clin. Pharmacol. 8, 177–189 (2016).
Fuji, R. N. et al. Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Sci. Transl Med. 7, 273ra215 (2015).
Ness, D. et al. Leucine-rich repeat kinase 2 (LRRK2)-deficient rats exhibit renal tubule injury and perturbations in metabolic and immunological homeostasis. PLOS ONE 8, e66164 (2013).
Di Maio, R. et al. LRRK2 activation in idiopathic Parkinson's disease. Sci. Transl Med. 10, eaar5429 (2018).
Denali Therapeutics Inc. Denali Therapeutics announces advancement and expansion of its LRRK2 inhibitor clinical program for Parkinson's disease. Denali Therapeutics http://investors.denalitherapeutics.com/node/6496/pdf (2017).
Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).
Sul, J. W. et al. Accumulation of the parkin substrate, FAF1, plays a key role in the dopaminergic neurodegeneration. Hum. Mol. Genet. 22, 1558–1573 (2013).
Park, H. S. et al. Assessment of potential protective effect on dopaminergic neuron by an Fas-associated factor 1 inhibitor treatment using [18F]FE-PE2I PET in a Parkinson's disease mouse model. J. Nuclear Med. 58 (Suppl. 1), 13 (2017).
Langston, J. W. The MPTP Story. J. Parkinsons Dis. 7 (Suppl. 1), 11–19 (2017).
Morissette, M. & Di Paolo, T. Non-human primate models of PD to test novel therapies. J. Neural Transm. 125, 291–324 (2017).
Close, S. P., Elliott, P. J., Hayes, A. G. & Marriott, A. S. Effects of classical and novel agents in a MPTP-induced reversible model of Parkinson's disease. Psychopharmacology 102, 295–300 (1990).
Gregoire, L., Jourdain, V. A., Townsend, M., Roach, A. & Di Paolo, T. Safinamide reduces dyskinesias and prolongs L-DOPA antiparkinsonian effect in parkinsonian monkeys. Parkinsonism Relat. Disord. 19, 508–514 (2013).
Fox, S. H. & Brotchie, J. M. The MPTP-lesioned non-human primate models of Parkinson's disease. Past, present, and future. 184, 133–157 (2010).
Ray Chaudhuri, K. et al. Non-oral dopaminergic therapies for Parkinson's disease: current treatments and the future. NPJ Parkinsons Dis. 2, 16023 (2016).
Pilleri, M. & Antonini, A. Novel levodopa formulations in the treatment of Parkinson's disease. Expert Rev. Neurother. 14, 143–149 (2014).
Tambasco, N., Romoli, M. & Calabresi, P. Levodopa in Parkinson's disease: current status and future developments. Curr. Neuropharmacol. 16, 1239–1252 (2017).
Schwarzschild, M. A., Agnati, L., Fuxe, K., Chen, J. F. & Morelli, M. Targeting adenosine A2A receptors in Parkinson's disease. Trends Neurosci. 29, 647–654 (2006).
Freitas, M. E. & Fox, S. H. Nondopaminergic treatments for Parkinson's disease: current and future prospects. Neurodegener. Dis. Manag. 6, 249–268 (2016).
Ko, W. K. et al. An evaluation of istradefylline treatment on Parkinsonian motor and cognitive deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque models. Neuropharmacology 110, 48–58 (2016).
Kondo, T., Mizuno, Y. & Japanese Istradefylline Study Group. A long-term study of istradefylline safety and efficacy in patients with Parkinson disease. Clin. Neuropharmacol. 38, 41–46 (2015).
Hauser, R. A., Hubble, J. P., Truong, D. D. & Istradefylline US-001 Study Group. Randomized trial of the adenosine A(2A) receptor antagonist istradefylline in advanced PD. Neurology 61, 297–303 (2003).
Kyowa Hakko Kirin Co., Ltd. Kyowa Hakko Kirin announces top-line results of global phase 3 trial of KW-6002 (Istradefylline) for Parkinson's disease. Kyowa Kirin http://kyowa-kirin.com/news_releases/2016/pdf/e20161213_01.pdf (2016).
Kyowa Hakko Kirin Co., Ltd. Kyowa Hakko Kirin announces the intent to file Istradefylline (KW-6002) for Parkinson's disease with the US FDA. Kyowa Kirin http://kyowa-kirin.com/news_releases/2017/pdf/e20171017_01.pdf (2017).
Hodgson, R. A. et al. Preladenant, a selective A(2A) receptor antagonist, is active in primate models of movement disorders. Exp. Neurol. 225, 384–390 (2010).
Hauser, R. A. et al. Preladenant in patients with Parkinson's disease and motor fluctuations: a phase 2, double-blind, randomised trial. Lancet Neurol. 10, 221–229 (2011).
Hauser, R. A. et al. Preladenant as an adjunctive therapy with levodopa in Parkinson disease: two randomized clinical trials and lessons learned. JAMA Neurol. 72, 1491–1500 (2015).
Hauser, R. A. et al. Tozadenant (SYN115) in patients with Parkinson's disease who have motor fluctuations on levodopa: a phase 2b, double-blind, randomised trial. Lancet Neurol. 13, 767–776 (2014).
Acorda Therapeutics Inc. Acorda discontinues tozadenant development program. Acord Therapeutics http://ir.acorda.com/investors/investor-news/investor-news-details/2017/Acorda-Discontinues-Tozadenant-Development-Program/default.aspx (2017).
Conn, P. J. & Pin, J. P. Pharmacology and functions of metabotropic glutamate receptors. Annu. Rev. Pharmacol. Toxicol. 37, 205–237 (1997).
Nicoletti, F. et al. Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology 60, 1017–1041 (2011).
Pin, J. P. & Acher, F. The metabotropic glutamate receptors: structure, activation mechanism and pharmacology. Curr. Drug Targets CNS Neurol. Disord. 1, 297–317 (2002).
Schoepp, D. D., Jane, D. E. & Monn, J. Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology 38, 1431–1476 (1999).
Picconi, B. & Calabresi, P. in Levodopa-Induced Dyskinesia in Parkinson's Disease (eds Fox, S. H. & Brotchie, J. M.) 229–243 (Springer, London, 2014).
Morin, N. & Di Paolo, T. Pharmacological treatments inhibiting levodopa-induced dyskinesias in MPTP-lesioned monkeys: brain glutamate biochemical correlates. Front. Neurol. 5, 144 (2014).
Litim, N., Morissette, M. & Di Paolo, T. Metabotropic glutamate receptors as therapeutic targets in Parkinson's disease: an update from the last 5 years of research. Neuropharmacology 115, 166–179 (2017).
Amalric, M. Targeting metabotropic glutamate receptors (mGluRs) in Parkinson's disease. Curr. Opin. Pharmacol. 20, 29–34 (2015).
Charvin, D. mGlu4 allosteric modulation for treating Parkinson's disease. Neuropharmacology 135, 308–315 (2018).
Duty, S. Targeting glutamate receptors to tackle the pathogenesis, clinical symptoms and levodopa-induced dyskinesia associated with Parkinson's disease. CNS Drugs 26, 1017–1032 (2012).
Fox, S. H. Non-dopaminergic treatments for motor control in Parkinson's disease. Drugs 73, 1405–1415 (2013).
Ory-Magne, F. et al. Withdrawing amantadine in dyskinetic patients with Parkinson disease: the AMANDYSK trial. Neurology 82, 300–307 (2014).
Vijayakumar, D. & Jankovic, J. Drug-induced dyskinesia, part 1: treatment of levodopa-induced dyskinesia. Drugs 76, 759–777 (2016).
Vale, J. A. & Maclean, K. S. Amantadine-induced heart-failure. Lancet 1, 548 (1977).
Flaherty, J. A. & Bellur, S. N. Mental side effects of amantadine therapy: its spectrum and characteristics in a normal population. J. Clin. Psychiatry 42, 344–345 (1981).
Xu, W. J., Wei, N., Xu, Y. & Hu, S. H. Does amantadine induce acute psychosis? A case report and literature review. Neuropsychiatr. Dis. Treat. 12, 781–783 (2016).
Krystal, J. H. et al. Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: implications for glutamatergic and dopaminergic model psychoses and cognitive function. Arch. Gen. Psychiatry 62, 985–994 (2005).
Blanpied, T. A., Clarke, R. J. & Johnson, J. W. Amantadine inhibits NMDA receptors by accelerating channel closure during channel block. J. Neurosci. 25, 3312–3322 (2005).
Pahwa, R. et al. ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson disease (EASE LID study): a randomized clinical trial. JAMA Neurol. 74, 941–949 (2017).
Pahwa, R. et al. Amantadine extended release for levodopa-induced dyskinesia in Parkinson's disease (EASED study). Mov. Disord. 30, 788–795 (2015).
Gubellini, P., Iskhakova, L., Smith, Y. & Amalric, M. in mGLU Receptors (The Receptors) 1st edn ( eds Ngomba, R. T., Di Giovanni, G., Battaglia, G., Nicoletti, F. ) Vol. 31 33–57 (Humana Press, Cham, 2017).
Conn, P. J., Battaglia, G., Marino, M. J. & Nicoletti, F. Metabotropic glutamate receptors in the basal ganglia motor circuit. Nat. Rev. Neurosci. 6, 787–798 (2005).
Gregoire, L. et al. The acute antiparkinsonian and antidyskinetic effect of AFQ056, a novel metabotropic glutamate receptor type 5 antagonist, in L-DOPA-treated parkinsonian monkeys. Parkinsonism Relat. Disord. 17, 270–276 (2011).
Berg, D. et al. AFQ056 treatment of levodopa-induced dyskinesias: results of 2 randomized controlled trials. Mov. Disord. 26, 1243–1250 (2011).
Bezard, E. et al. The mGluR5 negative allosteric modulator dipraglurant reduces dyskinesia in the MPTP macaque model. Mov. Disord. 29, 1074–1079 (2014).
Rascol, O. et al. Use of metabotropic glutamate 5-receptor antagonists for treatment of levodopa-induced dyskinesias. Parkinsonism Relat. Disord. 20, 947–956 (2014). This article provides a review on the evidence supporting the development of mGlu5 NAMs for the treatment of LIDs.
Tison, F. et al. A phase 2A trial of the novel mGluR5-negative allosteric modulator dipraglurant for levodopa-induced dyskinesia in Parkinson's disease. Mov. Disord. 31, 1373–1380 (2016).
Charvin, D. et al. Discovery, structure-activity relationship and anti-parkinsonian effect of a potent and brain-penetrant chemical series of positive allosteric modulators of metabotropic glutamate receptor 4. J. Med. Chem. 60, 8515–8537 (2017).
Charvin, D. et al. in 9th International Meeting On Metabotropic Glutamate Receptors (Sicily, Italy, 2017).
Charvin, D. et al. An mGlu4 positive allosteric modulator alleviates parkinsonism in primates. Mov. Disord. https://doi.org/10.1002/mds.27462 (2018). This article provides a complete characterization and the first evidence that an mGlu4 PAM has both antiparkinsonian and antidyskinetic efficacy in primates
Carta, M., Carlsson, T., Kirik, D. & Bjorklund, A. Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats. Brain 130, 1819–1833 (2007).
Kleedorfer, B., Lees, A. J. & Stern, G. M. Buspirone in the treatment of levodopa induced dyskinesias. J. Neurol. Neurosurg. Psychiatry 54, 376–377 (1991).
Paolone, G., Brugnoli, A., Arcuri, L., Mercatelli, D. & Morari, M. Eltoprazine prevents levodopa-induced dyskinesias by reducing striatal glutamate and direct pathway activity. Mov. Disord. 30, 1728–1738 (2015).
Svenningsson, P. et al. Eltoprazine counteracts L-DOPA-induced dyskinesias in Parkinson's disease: a dose-finding study. Brain 138, 963–973 (2015).
Chung, K. A., Lobb, B. M., Nutt, J. G. & Horak, F. B. Effects of a central cholinesterase inhibitor on reducing falls in Parkinson disease. Neurology 75, 1263–1269 (2010).
Moreau, C. et al. Methylphenidate for gait hypokinesia and freezing in patients with Parkinson's disease undergoing subthalamic stimulation: a multicentre, parallel, randomised, placebo-controlled trial. Lancet Neurol. 11, 589–596 (2012).
Hauser, R. A., Heritier, S., Rowse, G. J., Hewitt, L. A. & Isaacson, S. H. Droxidopa and reduced falls in a trial of Parkinson disease patients with neurogenic orthostatic hypotension. Clin. Neuropharmacol. 39, 220–226 (2016).
Albin, R. L., Young, A. B. & Penney, J. B. The functional anatomy of basal ganglia disorders. Trends Neurosci. 12, 366–375 (1989).
Graybiel, A. M. The basal ganglia. Curr. Biol. 10, R509–R511 (2000).
Kravitz, A. V. et al. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature 466, 622–626 (2010).
Cui, G. et al. Concurrent activation of striatal direct and indirect pathways during action initiation. Nature 494, 238–242 (2013). This study provides the first definitive evidence that direct and indirect pathway striatal neurons are co-activated during movement initiation and that an adequate coordination between both pathways is important for the execution of appropriate movements.
Cahill, E., Salery, M., Vanhoutte, P. & Caboche, J. Convergence of dopamine and glutamate signaling onto striatal ERK activation in response to drugs of abuse. Front. Pharmacol. 4, 172 (2014).
Cazorla, M., Kang, U. J. & Kellendonk, C. Balancing the basal ganglia circuitry: a possible new role for dopamine D2 receptors in health and disease. Mov. Disord. 30, 895–903 (2015).
Kim, J. et al. Inhibitory basal ganglia inputs induce excitatory motor signals in the thalamus. Neuron 95, 1181–1196 (2017).
Bateup, H. S. et al. Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors. Proc. Natl Acad. Sci. USA 107, 14845–14850 (2010).
Durieux, P. F. et al. D2R striatopallidal neurons inhibit both locomotor and drug reward processes. Nat. Neurosci. 12, 393–395 (2009).
Szewczyk-Krolikowski, K. et al. Functional connectivity in the basal ganglia network differentiates PD patients from controls. Neurology 83, 208–214 (2014).
Rana, A. Q., Ahmed, U. S., Chaudry, Z. M. & Vasan, S. Parkinson's disease: a review of non-motor symptoms. Expert Rev. Neurother. 15, 549–562 (2015).
Prakash, K. M., Nadkarni, N. V., Lye, W. K., Yong, M. H. & Tan, E. K. The impact of non-motor symptoms on the quality of life of Parkinson's disease patients: a longitudinal study. Eur. J. Neurol. 23, 854–860 (2016).
Erro, R. et al. The non-motor side of the honeymoon period of Parkinson's disease and its relationship with quality of life: a 4-year longitudinal study. Eur. J. Neurol. 23, 1673–1679 (2016).
Cummings, J. et al. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 383, 533–540 (2014).
Ghiglieri, V., Calabrese, V. & Calabresi, P. Alpha-synuclein: from early synaptic dysfunction to neurodegeneration. Front. Neurol. 9, 295 (2018). This paper provides an outlook of seminal and recent experimental studies that explore the roles of α-synuclein.
Angot, E., Steiner, J. A., Hansen, C., Li, J. Y. & Brundin, P. Are synucleinopathies prion-like disorders? Lancet Neurol. 9, 1128–1138 (2010).
Brundin, P., Melki, R. & Kopito, R. Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat. Rev. Mol. Cell Biol. 11, 301–307 (2010). This article marks the start of a new research area that is focused on the cell-to-cell propagation of protein aggregates in neurodegenerative diseases such as PD, Alzheimer disease or Huntington disease on the basis of observations of Lewy bodies in grafted neurons in PD.
Braak, H. et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197–211 (2003).
Steiner, J. A., Quansah, E. & Brundin, P. The concept of alpha-synuclein as a prion-like protein: ten years after. Cell Tissue Res. 373, 161–173 (2018).
Park, J. S., Davis, R. L. & Sue, C. M. Mitochondrial dysfunction in Parkinson's disease: new mechanistic insights and therapeutic perspectives. Curr. Neurol. Neurosci. Rep. 18, 21 (2018). This review focuses on recent advances in understanding of the role that mitochondrial dysfunction plays in the pathogenesis of both sporadic and familial PD.
Winklhofer, K. F. & Haass, C. Mitochondrial dysfunction in Parkinson's disease. Biochim. Biophys. Acta 1802, 29–44 (2010).
Pissadaki, E. K. & Bolam, J. P. The energy cost of action potential propagation in dopamine neurons: clues to susceptibility in Parkinson's disease. Front. Comput. Neurosci. 7, 13 (2013).
Bolam, J. P. & Pissadaki, E. K. Living on the edge with too many mouths to feed: why dopamine neurons die. Mov. Disord. 27, 1478–1483 (2012).
Surmeier, D. J., Guzman, J. N., Sanchez-Padilla, J. & Schumacker, P. T. The role of calcium and mitochondrial oxidant stress in the loss of substantia nigra pars compacta dopaminergic neurons in Parkinson's disease. Neuroscience 198, 221–231 (2011).
Audano, M., Schneider, A. & Mitro, N. Mitochondria, lysosomes and dysfunction: their meaning in neurodegeneration. J. Neurochem. https://doi.org/10.1111/jnc.14471 (2018).
Remondelli, P. & Renna, M. The endoplasmic reticulum unfolded protein response in neurodegenerative disorders and its potential therapeutic significance. Front. Mol. Neurosci. 10, 187 (2017).
Minakaki, G. et al. Autophagy inhibition promotes SNCA/alpha-synuclein release and transfer via extracellular vesicles with a hybrid autophagosome-exosome-like phenotype. Autophagy 14, 98–119 (2018).
Gao, F. et al. Mitophagy in Parkinson's disease: pathogenic and therapeutic implications. Front. Neurol. 8, 527 (2017).
Tarrade, A. et al. A mutation of spastin is responsible for swellings and impairment of transport in a region of axon characterized by changes in microtubule composition. Hum. Mol. Genet. 15, 3544–3558 (2006).
Morfini, G. A. et al. Axonal transport defects in neurodegenerative diseases. J. Neurosci. 29, 12776–12786 (2009).
Burre, J. The synaptic function of α-synuclein. J. Parkinsons Dis. 5, 699–713 (2015).
Guridi, J. & Alegre, M. Oscillatory activity in the basal ganglia and deep brain stimulation. Mov. Disord. 32, 64–69 (2017).
Picconi, B. et al. Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia. Nat. Neurosci. 6, 501–506 (2003).
Caligiore, D. et al. Parkinson's disease as a system-level disorder. NPJ Parkinsons Dis. 2, 16025 (2016).
Blandini, F., Nappi, G., Tassorelli, C. & Martignoni, E. Functional changes of the basal ganglia circuitry in Parkinson's disease. Prog. Neurobiol. 62, 63–88 (2000).
Mellone, M. & Gardoni, F. Glutamatergic mechanisms in L-DOPA-induced dyskinesia and therapeutic implications. J. Neural Transm. 125, 1225–1236 (2018).
Kaur, K., Gill, J. S., Bansal, P. K. & Deshmukh, R. Neuroinflammation - a major cause for striatal dopaminergic degeneration in Parkinson's disease. J. Neurol. Sci. 381, 308–314 (2017).
Przedborski, S. The two-century journey of Parkinson disease research. Nat. Rev. Neurosci. 18, 251–259 (2017).
Foltynie, T. & Athauda, D. Glucagon-like peptides (GLP-1) perspectives in synucleinopathies treatment. Mov. Disord. Clin. Pract. 5, 255–258 (2018).
Eskow, K. L., Gupta, V., Alam, S., Park, J. Y. & Bishop, C. The partial 5-HT(1A) agonist buspirone reduces the expression and development of l-DOPA-induced dyskinesia in rats and improves L-DOPA efficacy. Pharmacol. Biochem. Behav. 87, 306–314 (2007).
Prexton Therapeutics. Parkinson's disease: Prexton Therapeutics starts phase 1 clinical trial. Prexton Therapeutics http://www.prextontherapeutics.com/news/press_release/6-parkinson's_disease__prexton_therapeutics_starts_phase_1_clinical_trial.html (2016).
Prexton Therapeutics. Prexton announces initiation of phase II clinical testing in Parkinson's disease. Prexton Therapeutics http://www.prextontherapeutics.com/news/press_release/9-prexton_announces_initiation_of_phase_ii_clinical_testing_in_parkinson's_disease.html (2017).
Zesiewicz, T. A., Sullivan, K. L., Freeman, A. & Juncos, J. L. Treatment of imbalance with varenicline Chantix(R): report of a patient with fragile X tremor/ataxia syndrome. Acta Neurol. Scand. 119, 135–138 (2009).
Zhang, D. et al. Nicotinic receptor agonists reduce L-DOPA-induced dyskinesias in a monkey model of Parkinson's disease. J. Pharmacol. Exp. Ther. 347, 225–234 (2013).
Hubbard, D., Hacksell, U. & McFarland, K. Behavioral effects of clozapine, pimavanserin, and quetiapine in rodent models of Parkinson's disease and Parkinson's disease psychosis: evaluation of therapeutic ratios. Behav. Pharmacol. 24, 628–632 (2013).
McFarland, K., Price, D. L. & Bonhaus, D. W. Pimavanserin, a 5-HT2A inverse agonist, reverses psychosis-like behaviors in a rodent model of Parkinson's disease. Behav. Pharmacol. 22, 681–692 (2011).
Meltzer, H. Y. et al. Pimavanserin, a serotonin(2A) receptor inverse agonist, for the treatment of parkinson's disease psychosis. Neuropsychopharmacology 35, 881–892 (2010).
Stahl, S. M. Mechanism of action of pimavanserin in Parkinson's disease psychosis: targeting serotonin 5HT2A and 5HT2C receptors. CNS Spectr. 21, 271–275 (2016).
Weintraub, D. et al. in Thirtieth Annual Symposium on Etiology, Pathogenesis, and Treatment of Parkinson Disease and Other Movement Disorders (Portland, USA, 2016).
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D.C. thanks P. Hongaard for inspiring this Review.
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D.C. has received scientific grants from the Michael J. Fox Foundation (MJFF). D.C. and R.M. are members of the Management Team of Prexton Therapeutics. O.R. has received scientific grants from Agence Nationale de la Recherche, CHU de Toulouse, France-Parkinson, INSERM-DHOS Recherche Clinique Translationnelle, MJFF, Programme Hospitalier de Recherche Clinique and the European Commission (FP7, H2020). O.R. is a scientific adviser or consultant for AbbVie, Adamas Pharmaceuticals, Acorda Therapeutics, Addex Therapeutics, AlzProtect, ApoPharma, AstraZeneca, Bial, Biogen, Britannia, Clevexel, Cynapsus, INC Research, Lundbeck, Merck, MundiPharma, Neuroderm, Novartis, Oxford Biomedica, Parexel, Pfizer, Prexton Therapeutics, Quintiles, Sanofi, Servier, Teva, UCB, XenoPort and Zambon. R.A.H. reports consulting fees from Guidepoint Global, Gerson Lehrman Group, LCN Consulting, Putnam Associates, the National Parkinson Foundation, eResearch Technology, Inc., Lundbeck, Cynapsus, Sarepta Therapeutics, Adamas Pharmaceuticals, Neurocrine Biosciences, Back Bay Life Science, US WorldMeds, Biotie Therapies, MJFF, Neuropore Therapies, the US National Institutes of Health, Projects in Knowledge, Prexton Therapeutics, Acorda Therapeutics, Vista Research, LifeMax, Peerview Press, ClinicalMind Medical and Therapeutic Communications, Sunovion Pharmaceuticals, Inc., the Academy for Continued Healthcare Learning, Outcomes Insights, Expert Connect, HealthLogix, Teva, Cowen and Company, Pharma Two B, Ltd., Pfizer, RMEI Medical Education for Better Outcomes, ClearView Healthcare Partners, Health Advances, Kyowa Kirin Pharmaceutical Development, Ltd., Impax Laboratories, Quintiles, Pfizer, AbbVie, AstraZeneca, Eli Lilly & Company, Decision Resources Group, Seagrove Partners, LLC, Intec Pharma, Ltd., Schlesinger Associates, Huron Consulting Group, Pennside Partners, Bracket, Phase Five Communications, LCN Consulting and the Windrose Consulting Group.
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Glossary
- Bradykinesia
-
Abnormal slowness of movement.
- Autonomic dysfunction
-
Abnormal functioning of the autonomic nervous system, affecting the functioning of the heart, bladder, intestines, sweat glands, pupils and blood vessels. Examples include constipation, orthostatic hypotension, urinary incontinence and erectile dysfunction.
- Synucleinopathy
-
A neurodegenerative disease characterized by an excessive accumulation of α-synuclein. Examples include PD, dementia with Lewy bodies and multiple system atrophy.
- Dyskinesia
-
Abnormal involuntary movements. Levodopa-induced dyskinesia is associated with chronic levodopa treatment in patients with PD. It is characterized by hyperkinetic movements including chorea, athetosis and dystonia.
- Dopamine dysregulation syndrome
-
Dysfunction of the reward system associated with long-term dopaminergic treatments. It is characterized by addictive behaviours and excessive use of dopaminergic medication, with patients taking quantities of medication well beyond the dose required to treat their motor disabilities.
- Disease modification
-
Efficacy of a therapy in stopping, slowing or delaying disease progression, and therefore the clinical decline, through an effect on the underlying pathological process (either cellular protection or restoration of cellular function).
- Unified Parkinson Disease Rating Scale
-
(UPDRS). Used to assess severity and impact of PD signs and symptoms. It is made up of sections (parts I–IV) assessing different aspects of the disease.
- Methyl-4 phenyl 1,2,3,6 tetrahydropyridine
-
(MPTP). A neurotoxin that causes irreversible loss of dopamine neurons and parkinsonism in mice, monkeys and humans. The neurotoxicity of MPTP was first discovered when a young man self-injected an illicit narcotic (desmethylprodine (MPPP)) containing MPTP as a major impurity. He developed PD motor symptoms and responded to levodopa therapy, and the autopsy showed selective degeneration of dopaminergic neurons of the substantia nigra.
- ON/OFF
-
Alternating periods of good (ON) and poor (OFF) control of motor symptoms by levodopa treatment. ON refers to time when medication is providing benefit with regard to mobility, slowness and stiffness. OFF refers to time when a medication's efficacy has worn off and is no longer providing benefit with regard to mobility, slowness and stiffness.
- Type 2 diabetes mellitus
-
(T2DM). Type of diabetes that is characterized by insulin resistance in appropriate hepatic glucose production and impaired insulin secretion. Onset is usually after 40 years.
- Allosteric modulators
-
Molecules that bind a site that is different from the binding site of the endogenous agonist. As modulators, they act only in presence of the endogenous agonist, either potentiating (PAM) or reducing (NAM) the receptor response.
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Charvin, D., Medori, R., Hauser, R. et al. Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs. Nat Rev Drug Discov 17, 804–822 (2018). https://doi.org/10.1038/nrd.2018.136
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DOI: https://doi.org/10.1038/nrd.2018.136
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