Metabolism of Dopamine in Nucleus Accumbens Astrocytes Is Preserved in Aged Mice Exposed to MPTP

Parkinson disease (PD) is prevalent in elderly individuals and is characterized by selective degeneration of nigrostriatal dopamine (NSDA) neurons. Interestingly, not all dopamine (DA) neurons are affected equally by PD and aging, particularly mesolimbic (ML) DA neurons. Here, effects of aging were examined on presynaptic DA synthesis, reuptake, metabolism and neurotoxicant susceptibility of NSDA and mesolimbic dopamine (MLDA) neurons and astrocyte DA metabolism. There were no differences in phenotypic markers of DA synthesis, reuptake or metabolism in NSDA or MLDA neurons in aged mice, but MLDA neurons displayed lower DA stores. Astrocyte metabolism of DA to 3-methoxytyramine (3-MT) in the striatum was decreased in aged mice, but was maintained in the nucleus accumbens. Despite diminished DA vesicular storage capacity in MLDA neurons, susceptibility to acute neurotoxicant exposure was similar in young and aged mice. These results reveal an age- and neurotoxicant-induced impairment of DA metabolic activity in astrocytes surrounding susceptible NSDA neurons as opposed to maintenance of DA metabolism in astrocytes surrounding resistant MLDA neurons, and suggest a possible therapeutic target for PD

Iron and infection: effects of host iron status and the iron-regulatory genes haptoglobin and NRAMP1 (SLC11A1) on host-pathogen interactions in tuberculosis and HIV.

There are many lines of evidence illustrating that iron plays a pivotal role in modulating the battle for survival between mammalian hosts and their pathogens. Each displays considerable genetic investment in a wide range of mechanisms for acquiring and maintaining iron. These competitive mechanisms are highly complex, existing within an interacting matrix of absorption, transport, storage and detoxification systems, each of which are iron-responsive and thus able to adapt to the different phases of infection. Considerable genetic polymorphism in some of these systems, with signals of geographic selection in the hosts, and niche selection in the pathogens, indicates that they are critical for species survival. In this review we briefly summarize the role of iron in host immune function before reviewing the available evidence that iron modulates susceptibility and disease outcomes in HIV and TB (tuberculosis). We then examine the putative role of iron-related host genes by focussing on two candidate genes, haptoglobin and NRAMP1, for which there are common polymorphic variants in humans with strong evidence of functionally distinct biochemical phenotypes that would be predicted to influence the course of HIV and TB infections. Finally, we examine the limited evidence so far available that nutrient-gene interactions are likely to influence the way in which gene variants can protect against infection. We conclude that there is a wealth of evidence associating alterations in iron balance and in iron-regulatory systems with disease progression, but that many issues related to the direction of causality, mechanisms of action and sensitivity to pharmacological intervention remain to be elucidated. Since iron is probably the most widely prescribed compound throughout the world, used in both preventative and treatment regimens, a deeper understanding of the host-pathogen interactions relating to iron constitutes an important area for both basic and clinical research