Maneb potentiates paraquat neurotoxicity by inducing key Bcl-2 family members

An important feature of Parkinson's disease is the degeneration of dopaminergic neurons in the Substantia Nigra pars compacta. Paraquat (PQ) and MPTP cause the selective degeneration of these neurons in vivo, and combining PQ with maneb exacerbates that pathology. Elucidation of the cell death mechanisms involved is important to understand how multiple environmental toxins may contribute to sporadic Parkinson's disease. We recently reported that PQ induces neuronal apoptosis through Bak activation, in contrast to MPP+, the toxic metabolite of MPTP, which relies on Bax and p53. Here we show that individually PQ and maneb activate Bak, but together they trigger Bax-dependent cell death. Focusing on mechanisms responsible for this synergy, we found that maneb+PQ increased the expression of three strong Bak inhibitors, Bfl-1, Bcl-xL and Mcl-1, and also induced Bax activators that included Bik and Bim. Those responses favor Bax-dependent MOMP and apoptosis. SiRNA knockdown of Bax and Bak confirmed that individually PQ and maneb induce Bak-dependent cell death, but together they block the Bak pathway and activate apoptosis through Bax.