Evidence for dopaminergic axonal degeneration as an early pathological process in Parkinson's disease

Parkinson's disease is a common neurodegenerative disorder presenting with a variety of motor and non-motor symptoms. The motor symptoms manifest as a result of the progressive degeneration of midbrain dopaminergic neurons. The axons of these neurons project to the striatum as the nigrostriatal pathway, which is a crucial part of the basal ganglia circuitry controlling movement. In addition to the neuronal degeneration, abnormal intraneuronal a-synuclein protein inclusions called Lewy bodies and Lewy neurites increase in number and spread throughout the nervous system as the disease progresses. While the loss of midbrain dopaminergic neurons is well-established as being central to motor symptoms, there is an increasing focus on the timing of nigrostriatal degeneration, with preclinical evidence suggesting that early axonal degeneration may play a key role in the early stages of Parkinson's disease. Here we review recent evidence for early midbrain dopaminergic axonal degeneration in patients with Parkinson's disease, and explore the potential role of alpha-synuclein accumulation in this process, with a focus on studies in human populations at the imaging, post-mortem, cellular and molecular levels. Finally, we discuss the implications of this for neurotrophic factor therapies for Parkinson's disease.