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Molecular and clinical prodrome of Parkinson disease: implications for treatment

Nature Reviews Neurology volume 6, pages 309–317 (2010)Cite this article

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Abstract

The development of interventions to slow or prevent progression represents an important aim for current research into Parkinson disease (PD). General agreement prevails that success in this endeavor will depend on a clearer understanding of etiology and pathogenesis, and several important advances have recently been made, particularly in defining the genetic causes of PD. Studies of the biochemical consequences of the mutations that cause familial PD, and postmortem brain studies of idiopathic, sporadic PD, have highlighted mitochondrial dysfunction, oxidative stress, and protein metabolism by the ubiquitin–proteasomal and autophagy systems as being central to pathogenesis. In parallel with advances in etiopathogenesis, a clearer perception has developed of the clinical prodrome of PD, offering an opportunity to identify individuals who are at risk of PD, as well as those in the earliest clinical phase of the disease that might even precede the onset of motor symptoms. These populations are potentially the most suitable in which to test new protective therapies, and to study potential peripheral markers of disease progression. The awareness of the early symptomatic period of PD also raises the possibility of providing treatments that not only improve motor function but might also favorably modify outcome.

Key Points

  • The biochemical abnormalities that constitute the molecular prodrome of Parkinson disease (PD) can be initiated by genetic or environmental factors and seem to be common to familial and sporadic disease

  • The molecular prodrome will determine the pathology that evolves in PD and the associated cell dysfunction and death

  • The clinical prodrome will, in turn, reflect the evolving molecular and pathological prodromes and offers an important opportunity for early detection and therapeutic intervention

  • Future symptomatic and disease-modifying or neuroprotective drugs are likely to be based on interventions designed to interrupt the evolution of the molecular and pathological prodromes

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Figure 1: A model for α-synuclein breakdown pathways.
Figure 2: Interconnecting pathways of Parkinson disease pathogenesis.

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  1. Department of Clinical Neurosciences, Institute of Neurology, University College Medical School, Rowland Hill Street, London, NW3 2PF, UK

    Anthony H. V. Schapira

  2. Neurology Service, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Hospital Clínic, IDIBAPS, University of Barcelona, Villaroel 170, Barcelona, 08036, Spain

    Eduardo Tolosa

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A. H. V. Schapira has acted as a consultant for and received honoraria from Boehringer, GlaxoSmithKline, Novartis-Orion and Teva-Lundbeck, and has received research support from Boehringer and Teva-Lundbeck. E. Tolosa declares no competing interests.

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Schapira, A., Tolosa, E. Molecular and clinical prodrome of Parkinson disease: implications for treatment. Nat Rev Neurol 6, 309–317 (2010). https://doi.org/10.1038/nrneurol.2010.52

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