Transgenic Mice Overexpressing the Divalent Metal Transporter 1 Exhibit Iron Accumulation and Enhanced Parkin Expression in the Brain.

Exposure to divalent metals such as iron and manganese is thought to increase the risk for Parkinson's disease (PD). Under normal circumstances, cellular iron and manganese uptake is regulated by the divalent metal transporter 1 (DMT1). Accordingly, alterations in DMT1 levels may underlie the abnormal accumulation of metal ions and thereby disease pathogenesis. Here, we have generated transgenic mice overexpressing DMT1 under the direction of a mouse prion promoter and demonstrated its robust expression in several regions of the brain. When fed with iron-supplemented diet, DMT1-expressing mice exhibit rather selective accumulation of iron in the substantia nigra, which is the principal region affected in human PD cases, but otherwise appear normal. Alongside this, the expression of Parkin is also enhanced, likely as a neuroprotective response, which may explain the lack of phenotype in these mice. When DMT1 is overexpressed against a Parkin null background, the double-mutant mice similarly resisted a disease phenotype even when fed with iron- or manganese-supplemented diet. However, these mice exhibit greater vulnerability toward 6-hydroxydopamine-induced neurotoxicity. Taken together, our results suggest that iron accumulation alone is not sufficient to cause neurodegeneration and that multiple hits are required to promote PD.

Pharmacological or Genetic Activation of Hsp70 Protects against Loss of Parkin Function.

Mutations of parkin are a prevalent genetic contributor to familial Parkinson's disease (PD). As a key regulator of protein and mitochondrial homeostasis, parkin plays a pivotal role in maintaining dopaminergic neuronal survival. However, whereas Drosophila parkin null mutants exhibit prominent parkinsonian features, parkin-deficient mice generally lack an overt phenotype. Here, we found that the expression of Hsp70 along with several other members of the chaperone family is elevated in parkin null mice, suggesting a possible compensatory mechanism for the loss of parkin function in these mice that could have masked their phenotype. Supporting this, we demonstrate that the enhancement of chaperone function induced either pharmacologically via 17-AAG treatment or genetically via Hsp70 overexpression can protect cells against proteolytic and mitochondrial stress in a manner that is similar to that brought about by parkin overexpression. Importantly, we further showed that enhanced chaperone activity can ameliorate the pathological phenotypes in Drosophila parkin null mutants, which suggests the ability of chaperones to phenocopy parkin function. Taken together, our results suggest that Hsp members may act as compensatory factors for parkin loss of function and that the exploitation of these factors may be of potential therapeutic value.