Present and future approaches to Parkinson disease From molecular insights to new therapeutic avenues

Parkinson disease (PD) is a disorder of unknown cause affecting 1% of people over the age of 60 and 2% of people over the age of 70. Michael J. Fox and Muhammad Ali notwithstanding, PD is mainly a disease of aging, and aging is the greatest risk factor for PD (for example, Pope John Paul II [age 84], Billy Graham [age 85], and Salvatore Dali [age 85]). The disease was first described by James Parkinson in 1817 at the dawn of the Industrial Revolution.1 Parkinson’s genius lay in distinguishing the cardinal symptoms of the disease; e.g., slowness of movement, impaired gait, and tremor, from similar symptoms sometimes associated with normal aging. Parkinson disease, when fully developed, is readily recognizable, but until it was described by Parkinson it had escaped recognition by two millennia of physicians, from Hippocrates to Galen to Harvey. This suggests to some that PD did not exist before the Industrial Revolution. To others, it suggests that, until recently, very few people lived long enough to develop PD. In the two centuries since Parkinson described it, our understanding of PD has developed in parallel to our understanding of the brain. Indeed, insights from PD have provided a window into the brain; the anatomy, the chemistry, the pharmacology, and the molecular genetics of PD driving the development of neuroscience. In the nineteenth century, because of a lack of knowledge of the pathology and physiology of the brain and in the absence of an anatomic localization for PD, many neurologists believed that PD was either a disease of the muscles or a neurosis. In the 1870’s, Jean-Martin Charcot, the preeminent neurologist of that century, confirmed Parkinson’s observation, named the disease after Parkinson, and developed its first treatment; the belladonna alkaloids. Charcot’s work implied that PD had both an anatomic …