Parkinson Disease-associated Toxic Exposures Selectively Up-regulate Vesicular Glutamate Transporter VGlut2 in a Model of Human Cortical Neurons

Parkinson disease (PD) is the second most common neurodegenerative disease, characterized by both motor and cognitive features. Motor symptoms primarily involve midbrain dopaminergic neurons, while cognitive dysfunction involves cortical neurons. Environmental factors are important contributors to PD risk. In rodents, rare midbrain dopaminergic neurons that coexpress the vesicular glutamate transporter 2 (vGlut2) are resistant to various toxins that induce dopaminergic neurodegeneration. However, it is unclear how, and with what degree of specificity, cortical glutamatergic neurons respond to PD-associated exposures with respect to vGlut2. Here, we found that vGlut2 in stem cell-derived human cortical-like glutamatergic neurons was up-regulated in a highly specific manner to certain PD-related chemicals, such as rotenone, but not others, such as paraquat. Further, exposure to recombinant preformed fibrils of alpha-synuclein (αS), a protein accumulating in PD, also increased vGlut2, while fibrils from non-PD-related proteins did not. This effect did not involve templated aggregation of endogenous αS. Finally, the knockdown of vGlut2 sensitized cortical neurons to rotenone, supporting a functional role in resilience. Thus, up-regulation of vGlut2 occurs in a highly selective manner in response to specific PD-associated exposures in a model of cortical glutamatergic neurons, a key cell type for understanding PD dementia.