However, this comparison needs to take into account that PD is a degenerative disease, therefore Ndfip1 upregulation here might also serve totally different functions. For instance, failure of the ubiquitin proteasome system is linked to PD pathology, therefore Ndfip1 upregulation may represent a reactive response to further accelerate Nedd4-mediated ubiquitination for substrate trafficking or degradation. Alternatively, Ndfip1 response could result in the ubiquitination of DMT1, but failure of the ubiquitin proteosome system may prevent efficient degradation of the metal transporter. It should also be noted that Ndfip1 has a number of other protein targets, including PTEN a major tumor suppressor protein which has roles in cell survival pathways, as such the role of Ndfip1 in PD could be multifaceted and involve divergent pathways within the cell. These questions require testing using genetic tools in rodent models of PD. Finally, the expression of Ndfip1 in astrocytes of PD brains is an unexpected finding given that in healthy brains, Ndfip1 has never been encountered in non-neuronal elements in either the forebrain or midbrain. A number of explanations need to be considered for this response. It is possible that de novo Ndfip1 expression occurs in astrocytes in response to the RWJ 64809 disease process, and in particular to abnormal a-synuclein accumulation. The role that astrocytes play in PD is currently debated, but it is known that astrocytes can accumulate a-synuclein causing the recruitment of phagocytic microglia that can attack neurons in selected brain regions. The mechanism of Ndfip1 activation and function in astrocytes during PD is not clear, however astrocytes are also known to express DMT1 and it is possible that Ndfip1 in astrocytes has similar functions as in neurons, to regulate DMT1 and limit the entry of metals. In conclusion, we report that Ndfip1 is upregulated in dopaminergic neurons undergoing stress in the substantia nigra, the region of major neuronal loss in PD patients. Unexpectedly, Ndfip1 was also upregulated in astrocytes, a cell type not previously known to express the protein. The link between increased iron levels in PD and Ndfip1 function, suggests that DMT1 ubiquitination by Ndfip1/Nedd4-system may be involved in cell protection pathways to prevent metal toxicity. Sensory and motor information processed by the cortex and thalamus passes through the striatum where it is modulated by two largely antagonistic classes of MSNs that express distinct dopamine receptors and neuropeptides. The activity of the two classes of MSNs is modulated by dopaminergic input from the ventral midbrain as well as various populations of striatal interneurons. Both classes of MSNs send GABAergic projections to brain regions outside the striatum, which ultimately project back onto the thalamus and cortex. Through its modulation of cortical and thalamic input, and via downstream neural circuitry, the striatum contributes to the generation of goal-directed behavior.