How Parkinsonian toxins dysregulate the autophagy machinery.
Since their discovery, Parkinsonian toxins (6-hydroxydopamine, MPP+, paraquat, and rotenone) have been widely employed as in vivo and in vitro chemical models of Parkinson's disease (PD). Alterations in mitochondrial homeostasis, protein quality control pathways, and more recently, autophagy/mitophagy have been implicated in neurotoxin models of PD. Here, we highlight the molecular mechanisms by which different PD toxins dysregulate autophagy/mitophagy and how alterations of these pathways play beneficial or detrimental roles in dopamine neurons. The convergent and divergent effects of PD toxins on mitochondrial function and autophagy/mitophagy are also discussed in this review. Furthermore, we propose new diagnostic tools and discuss how pharmacological modulators of autophagy/mitophagy can be developed as disease-modifying treatments for PD. Finally, we discuss the critical need to identify endogenous and synthetic forms of PD toxins and develop efficient health preventive programs to mitigate the risk of developing PD.
Department of Pharmacology, University of Nevada School of Medicine, Manville Building 18A, Reno, NV 89557, USA. rdagda@medicine.nevada.edu.
Ruben K
RK
Dagda
Tania
T
Das Banerjee
Elzbieta
E
Janda
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D006801:Humans; D020267:MPTP Poisoning / Q000473:pathology; D008694:Methamphetamine / Q000633:toxicity; D063306:Mitophagy / Q000187:drug effects*; D009498:Neurotoxins / Q000008:administration & dosage*; D016627:Oxidopamine / Q000633:toxicity; D010269:Paraquat / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000209:etiology / Q000473:pathology*; D012402:Rotenone / Q000633:toxicity
D009498:Neurotoxins; D012402:Rotenone; D008694:Methamphetamine; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D010269:Paraquat