In 1817, the London surgeon James Parkinson published An Essay on the Shaking Palsy, describing six patients with a previously unrecognized syndrome: resting tremor, rigidity, bradykinesia (slowness of movement), postural instability. The disease that bears his name now affects roughly 10 million people worldwide. Its strangest feature is what underlies the symptoms: by the time motor signs first appear, roughly 80% of the dopamine-producing neurons in a small midbrain nucleus have already died. The condition is, clinically, the visible end of a long invisible process.
Parkinson's is the canonical synucleinopathy: degeneration of the dopaminergic neurons of the substantia nigra pars compacta, with intracellular Lewy bodies — aggregates of misfolded α-synuclein — as the pathological hallmark. The dopamine deficit in the basal ganglia produces the motor triad. As pathology spreads from brainstem to cortex (the Braak staging), patients increasingly develop cognitive impairment; Lewy-body dementia sits on the same disease spectrum, with prominent cognitive and visual-hallucination features alongside motor symptoms. Genetics matters in 10–15% of cases (LRRK2, GBA, SNCA, PARK2, others); the rest are sporadic, with environmental risk factors (pesticide exposure, head trauma) and protective factors (caffeine, exercise, smoking — the latter not a recommendation) more suggestive than determinative. Why dopamine neurons specifically die — the question of selective vulnerability — remains substantially unexplained after a century of research.
L-DOPA, introduced in 1967, remains the mainstay treatment — it dramatically improves motor symptoms but does not slow disease progression, and produces dyskinesias after long use. Deep brain stimulation of the subthalamic nucleus or globus pallidus interna helps refractory motor symptoms. Gene therapy, stem-cell approaches (transplanting iPSC-derived dopamine neurons), and α-synuclein-targeted antibodies are in clinical trials; results so far are modest. The clinical reality is largely unchanged from 1967: symptomatic management of a disease whose underlying biology we still cannot stop.