Biology of Parkinson's disease: pathogenesis and pathophysiology of a multisystem neurodegenerative disorder

Abstract

Parkinson's disease (PD) is the second most common movement disorder. The characteristic motor impairments - bradykinesia, rigidity, and resting tremor - result from degenerative loss of midbrain dopamine (DA) neurons in the substantia nigra, and are responsive to symptomatic treatment with dopaminergic medications and functional neurosurgery. PD is also the second most common neurodegenerative disorder. Viewed from this perspective, PD is a disorder of multiple functional systems, not simply the motor system, and of multiple neurotransmitter systems, not merely that of DA. The characteristic pathology - intraneuronal Lewy body inclusions and reduced numbers of surviving neurons - is similar in each of the targeted neuron groups, suggesting a common neurodegenerative process. Pathological and experimental studies indicate that oxidative stress, proteolytic stress, and inflammation figure prominently in the pathogenesis of PD. Yet, whether any of these mechanisms plays a causal role in human PD is unknown, because to date we have no proven neuroprotective therapies that slow or reverse disease progression in patients with PD. We are beginning to understand the pathophysiology of motor dysfunction in PD, but its etiopathogenesis as a neurodegenerative disorder remains poorly understood.