A dual-hit animal model for age-related parkinsonism

Parkinson's disease is a neurological disorder which afflicts an increasing number of individuals. If the wider complex of extrapyramidal symptoms referred to as “age-related parkinsonism” is included, the incidence is near 50% of the population above 80 years of age. This review summarizes recent studies from our laboratories as well as other research groups in the quest to explore the multi-faceted etiology of age-related neurodegeneration, in general, and degeneration of the substantia nigra dopaminergic neurons, in particular. Our work during recent years has focused on assessment of potential interactive effects of a reduction in glial cell line-derived neurotrophic factor (GDNF) and the aging process (intrinsic factors) and early neurotoxin exposure (an extrinsic factor) on dopamine (DA) systems and the behaviors they mediate. The guiding hypothesis directing the research to be described was that a combination of the two factors would exacerbate the decline in the DA transmitter system function that occurs during aging. The results obtained were consistent with the well-established aging-related decline in function and structure of neurons utilizing DA as a transmitter and motor function, and extended knowledge by establishing that the genetic reduction of Gdnf exacerbated these aging related changes. Thus, GDNF reduction appears to increase the vulnerability of the DA neurons to the many different challenges associated with the aging process. Assessment of methamphetamine effects on young Gdnf+/− mice indicated that reduced GDNF availability increased the vulnerability of DA systems to this well-established neurotoxin. The work discussed in this review is consistent with earlier work demonstrating the importance of GDNF for maintenance of DA neurons and also provides a novel model for progressive DA degeneration and motor dysfunction.