BAX channel activity mediates lysosomal disruption linked to Parkinson disease
Autophagy. 2014-03-26; 10(5): 889-900
DOI: 10.4161/auto.28286
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Lysosomal disruption is increasingly regarded as a major pathogenic event in
Parkinson disease (PD). A reduced number of intraneuronal lysosomes, decreased
levels of lysosomal-associated proteins and accumulation of undegraded
autophagosomes (AP) are observed in PD-derived samples, including fibroblasts,
induced pluripotent stem cell-derived dopaminergic neurons, and post-mortem brain
tissue. Mechanistic studies in toxic and genetic rodent PD models attribute
PD-related lysosomal breakdown to abnormal lysosomal membrane permeabilization
(LMP). However, the molecular mechanisms underlying PD-linked LMP and subsequent
lysosomal defects remain virtually unknown, thereby precluding their potential
therapeutic targeting. Here we show that the pro-apoptotic protein BAX
(BCL2-associated X protein), which permeabilizes mitochondrial membranes in PD
models and is activated in PD patients, translocates and internalizes into
lysosomal membranes early following treatment with the parkinsonian neurotoxin
MPTP, both in vitro and in vivo, within a time-frame correlating with LMP,
lysosomal disruption, and autophagosome accumulation and preceding mitochondrial
permeabilization and dopaminergic neurodegeneration. Supporting a direct
permeabilizing effect of BAX on lysosomal membranes, recombinant BAX is able to
induce LMP in purified mouse brain lysosomes and the latter can be prevented by
pharmacological blockade of BAX channel activity. Furthermore, pharmacological
BAX channel inhibition is able to prevent LMP, restore lysosomal levels, reverse
AP accumulation, and attenuate mitochondrial permeabilization and overall
nigrostriatal degeneration caused by MPTP, both in vitro and in vivo. Overall,
our results reveal that PD-linked lysosomal impairment relies on BAX-induced LMP,
and point to small molecules able to block BAX channel activity as potentially
beneficial to attenuate both lysosomal defects and neurodegeneration occurring in
PD.