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The ongoing pursuit of neuroprotective therapies in Parkinson disease

Key Points

  • Incomplete understanding of the pathogenesis of Parkinson disease (PD), lack of accurate animal models and validated biomarkers, and limitations in trial design impede the development of effective neuroprotective therapies for PD

  • Novel transgenic animal models, adaptive and delayed-start trial designs, and identification of potential serum, cerebrospinal fluid and neuroimaging biomarkers are facilitating development and testing of effective disease-modifying therapies

  • α-Synuclein has a key role in the pathogenesis of PD; targeting of the formation and clearance of this protein has shown promising results in preclinical models

  • Possible approaches for targeting α-synuclein accumulation include direct blocking of α-synuclein aggregation, immunization against α-synuclein, and enhancement of its lysosomal clearance; these strategies are all still in their infancy

  • As 50% of patients with PD have comorbid Alzheimer disease (AD) pathology, targeting of tau and amyloid-β could open novel avenues to alleviate or halt cognitive dysfunction

  • Disease-modifying therapies under investigation in AD could also be of benefit in PD; repurposing of existing drugs for use in PD also warrants further investigation

Abstract

Many agents developed for neuroprotective treatment of Parkinson disease (PD) have shown great promise in the laboratory, but none have translated to positive results in patients with PD. Potential neuroprotective drugs, such as ubiquinone, creatine and PYM50028, have failed to show any clinical benefits in recent high-profile clinical trials. This 'failure to translate' is likely to be related primarily to our incomplete understanding of the pathogenic mechanisms underlying PD, and excessive reliance on data from toxin-based animal models to judge which agents should be selected for clinical trials. Restricted resources inevitably mean that difficult compromises must be made in terms of trial design, and reliable estimation of efficacy is further hampered by the absence of validated biomarkers of disease progression. Drug development in PD dementia has been mostly unsuccessful; however, emerging biochemical, genetic and pathological evidence suggests a link between tau and amyloid-β deposition and cognitive decline in PD, potentially opening up new possibilities for therapeutic intervention. This Review discusses the most important 'druggable' disease mechanisms in PD, as well as the most-promising drugs that are being evaluated for their potential efficiency in treatment of motor and cognitive impairments in PD.

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Figure 1: Proposed mechanisms involved in the Parkinson disease pathogenesis, and targets for intervention.

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Acknowledgements

T.F. has received grants from the Michael J. Fox Foundation, Brain Research Trust, Cure Parkinson's Trust, Parkinson's UK and European Commission FP7.

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D.A. researched data for article. D.A. and T.F. substantially contributed to discussion of content and wrote the article. T.F. reviewed and edited the manuscript before submission.

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Correspondence to Thomas Foltynie.

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T.F. has received honoraria from Abbvie, Genus, Medtronic, Novartis, St. Jude Medical and Teva. D.A. declares no competing interests.

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Athauda, D., Foltynie, T. The ongoing pursuit of neuroprotective therapies in Parkinson disease. Nat Rev Neurol 11, 25–40 (2015). https://doi.org/10.1038/nrneurol.2014.226

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