title: BAX channel activity mediates lysosomal disruption linked to Parkinson disease.
abstract: 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.
authors.affiliation: Neurodegenerative Diseases Research Group; Vall d'Hebron Research Institute-CIBERNED; Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Bové
authors.affiliation: Neurodegenerative Diseases Research Group; Vall d'Hebron Research Institute-CIBERNED; Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Martínez-Vicente
authors.affiliation: Neurodegenerative Diseases Research Group; Vall d'Hebron Research Institute-CIBERNED; Barcelona, Spain.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dehay
authors.affiliation: Neurodegenerative Diseases Research Group; Vall d'Hebron Research Institute-CIBERNED; Barcelona, Spain.
authors.forename: Celine
authors.initials: C
authors.lastname: Perier
authors.affiliation: Neurodegenerative Diseases Research Group; Vall d'Hebron Research Institute-CIBERNED; Barcelona, Spain.
authors.forename: Ariadna
authors.initials: A
authors.lastname: Recasens
authors.affiliation: Merck Serono S.A.; Geneva Research Center; Geneva, Switzerland.
authors.forename: Agnes
authors.initials: A
authors.lastname: Bombrun
authors.affiliation: Merck Serono S.A.; Geneva Research Center; Geneva, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Antonsson
authors.affiliation: Neurodegenerative Diseases Research Group; Vall d'Hebron Research Institute-CIBERNED; Barcelona, Spain; Department of Biochemistry and Molecular Biology; Autonomous University of Barcelona; Barcelona, Spain; Catalan Institution for Research and Advanced Studies (ICREA); Barcelona, Spain.
authors.forename: Miquel
authors.initials: M
authors.lastname: Vila
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D010539:Permeability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism / Q000502:physiology*
chemical_list: D007473:Ion Channels; D051028:bcl-2-Associated X Protein; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
keywords: BAX channel inhibitor; MPTP; Parkinson disease; lysosome; mitochondria; neurodegeneration