Parkinson's Disease

James Parkinson's 'shaking palsy', the loss of dopamine neurons, alpha-synuclein and Lewy bodies, motor and non-motor symptoms, and treatments from L-dopa to deep brain stimulation.

The shaking palsy

In 1817 the London surgeon James Parkinson published An Essay on the Shaking Palsy, describing six people with tremor, a stooped posture and shuffling gait. The French neurologist Jean-Martin Charcot later named the condition after him. The World Health Organization estimated that over 8.5 million people were living with Parkinson's in 2019, and its prevalence has been rising faster than that of any other neurological disorder.

What goes wrong

The disease's hallmark is the loss of dopamine neurons in the substantia nigra, which supply dopamine to the basal ganglia. By the time symptoms appear, a large proportion of these neurons — often estimated at over half — have already died. Surviving neurons contain Lewy bodies, clumps of a misfolded protein called alpha-synuclein. Alpha-synuclein pathology may begin outside the brain — in the gut or the olfactory system — years before motor symptoms, according to one influential hypothesis by Heiko Braak. In 2023, a spinal fluid test detecting misfolded alpha-synuclein ("seed amplification assay") was shown to identify the disease with high accuracy.

Symptoms

Motor: slowness of movement (bradykinesia), rigidity, a resting tremor (often "pill-rolling" in one hand), and later balance problems, a shuffling gait and "freezing". Non-motor symptoms are common and often begin first: loss of smell, constipation, acting out dreams (REM sleep behaviour disorder), depression and anxiety; later, many people develop cognitive problems.

Causes

Most cases have no single cause; ageing, genetic susceptibility and environmental factors combine. Mutations in genes such as LRRK2, GBA1 and SNCA cause or raise risk in some families. Exposure to certain pesticides and solvents has been associated with higher risk. In the 1980s, young drug users who injected a contaminated synthetic opioid containing MPTP developed sudden severe parkinsonism — a tragic accident that gave researchers an important model.

Treatment

L-dopa (levodopa), introduced in the late 1960s, is converted to dopamine in the brain and remains the most effective drug, often combined with carbidopa. Over years, its effects can wear off between doses and cause involuntary movements (dyskinesias). Other drugs mimic dopamine or slow its breakdown. Deep brain stimulation of the subthalamic nucleus or globus pallidus helps many with advanced disease; in 2025 the US FDA approved an "adaptive" system that adjusts stimulation based on the brain's own signals. Exercise is strongly recommended. Treatments that slow the disease, and cell replacement therapies, are in clinical trials.