Mechanisms of Selective Toxicity in Neurodegenerative Disorders

Idiopathic Parkinson’s disease (PD) and related neurodegenerative disorders are characterized clinically by insidious onset and relentless advance that presumably reflect an ever-increasing loss of neuronal connectivity. Disconnection of neural pathways may result from primary degeneration of dendrites, neuronal perikarya, axons, or nerve terminals. Specificity of neuronal damage appears to be linked to factors such as: the structure and potency of the agent; the architecture, size, and activity of the neuronal pathway; and the presence of neuronal receptors and transporters for neurotransmitters and other molecules. Foreign substances that perturb axonal transport are associated with distal, retrograde (dying-back) degeneration, while those that interfere with glutamate neurotransmission may compromise dendritic integrity and trigger neuronal degeneration. Neither type of agent appears to be able to induce a progressive neuronal disease, a property that might be associated with substances that up-regulate the neuronal response to glutamate neurotransmission by persistently interfering with nucleic acid function. Discovery of environmental factors that act on normal or susceptible genotypes to trigger PD and related neurodegenerative disorders may open the way for disease prevention.