VTA neurons show a potentially protective transcriptional response to MPTP

Abstract

Parkinson's disease and its characteristic symptoms are thought to arise from the progressive degeneration of specific midbrain dopamine (DA) neurons. In humans, DA neurons of the substantia nigra (SN) and their projections to the striatum show selective vulnerability, while neighboring DA neurons of the ventral tegmental area (VTA) are relatively spared from degeneration. This pattern of cell loss is mimicked in humans, primates, and certain rodents by the neurotoxin MPTP. In this study, we aimed to test the hypothesis that there are factors in the VTA that are potentially neuroprotective against MPTP and that these factors change over time. We have found a dynamic transcriptional response within the cells of the VTA to sustained exposure to a low dose of MPTP. Specifically, the VTA has increased expression of 148 genes as an early response to MPTP and 113 genes as a late response to MPTP toxicity. This response encompasses many areas of cellular function, including protein regulation ( Phf6) and ion/metal regulation ( PANK2 and Car4). Notably, these responses were largely absent from the cells of the SN. Our data show a clear dynamic response in maintaining the homeostasis and viability of the neurons in the VTA that is lacking in the SN after neurotoxin challenge.