Figure 6. Proposed lysosomal and mitochondrial pathogenic role of BAX and therapeutic action of Bci in experimental PD. Early following MPTP treatment, activated BAX translocates to both lysosomal and mitochondrial membranes causing LMP and MOMP, respectively. BAX-induced LMP leads to a decreased number of lysosomes and subsequent accumulation of undegraded AP, eventually leading to the formation of protein aggregates. Besides impairing lysosomal-mediated degradation, BAX-induced LMP directly contributes to dopaminergic cell death by the leakage of lysosomal proteases into the cytosol, some of which, such as CTSB and CTSD, can remain active at neutral cytosolic pH and cause the digestion of vital proteins or the activation of additional hydrolases, including caspases. In turn, MOMP results in CYCS release and activation of caspase-dependent dopaminergic cell death. Pharmacological blockade of BAX channel activity with Bci is able to prevent both LMP and MOMP, restore lysosomal levels, reverse AP accumulation, and attenuate overall nigrostriatal dopaminergic neurodegeneration caused by MPTP. See main text for details. Dashed arrows correspond to currently unknown mechanisms.