title: The rescue of microtubule-dependent traffic recovers mitochondrial function in Parkinson's disease.
abstract: In Parkinson's disease mitochondrial dysfunction can lead to a deficient ATP supply to microtubule protein motors leading to mitochondrial axonal transport disruption. Compromised axonal transport will then lead to a disorganized distribution of mitochondria and other organelles in the cell, as well as, the accumulation of aggregated proteins like alpha-synuclein. Moreover, axonal transport disruption can trigger synaptic accumulation of autophagosomes packed with damaged mitochondria and protein aggregates promoting synaptic failure. We previously observed that neuronal-like cells with an inherent mitochondrial impairment derived from PD patients contain a disorganized microtubule network, as well as, alpha-synuclein oligomer accumulation. In this work we provide new evidence that an agent that promotes microtubule network assembly, NAP (davunetide), improves microtubule-dependent traffic, restores the autophagic flux and potentiates autophagosome-lysosome fusion leading to autophagic vacuole clearance in Parkinson's disease cells. Moreover, NAP is capable of efficiently reducing alpha-synuclein oligomer content and its sequestration by the mitochondria. Most interestingly, NAP decreases mitochondrial ubiquitination levels, as well as, increases mitochondrial membrane potential indicating a rescue in mitochondrial function. Overall, we demonstrate that by improving microtubule-mediated traffic, we can avoid mitochondrial-induced damage and thus recover cell homeostasis. These results prove that NAP may be a promising therapeutic lead candidate for neurodegenerative diseases that involve axonal transport failure and mitochondrial impairment as hallmarks, like Parkinson's disease and related disorders.
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
authors.forename: A R
authors.initials: AR
authors.lastname: Esteves
authors.forename: I
authors.initials: I
authors.lastname: Gozes
authors.forename: S M
authors.initials: SM
authors.lastname: Cardoso
mesh_terms: D000368:Aged; D001343:Autophagy / Q000187:drug effects; D016022:Case-Control Studies; D002460:Cell Line; D005260:Female; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D054875:Ubiquitination / Q000187:drug effects; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D009842:Oligopeptides; D051844:alpha-Synuclein; C425904:davunetide
keywords: (control cybrids); (sporadic Parkinson's disease cybrids); 1-methyl-4-phenylpyridinium; ASYN; CT cybrids; MPP(+); Microtubule network; Mitochondria dynamics; NAP; PD; Parkinson's disease; alpha-synuclein; mitochondrial DNA; mtDNA; sPD cybrids