title: Impairment of mitochondria dynamics by human A53T α-synuclein and rescue by NAP (davunetide) in a cell model for Parkinson's disease.
abstract: The formation of oligomers and aggregates of overexpressed or mutant α-synuclein play a role in the degeneration of dopaminergic neurons in Parkinson's disease by causing dysfunction of mitochondria, reflected in their disturbed mobility and production of ROS. The mode of action and mechanisms underlying this mitochondrial impairment is still unclear. We have induced stable expression of wild-type, A30P or A53T α-synuclein in neuronally differentiated SH-SY5Y neuroblastoma cells and studied anterograde and retrograde mitochondrial trafficking in this cell model for Parkinson's disease. In contrast to wild-type and A30P, A53T α-synuclein significantly inhibited mitochondrial trafficking, at first retrogradely and in a later stage anterogradely. Accordingly, A53T α-synuclein also caused the highest increase in ROS production in the dysmobilized mitochondria in comparison to wild-type or A30P α-synuclein. Treatment with NAP, the eight amino acid peptide identified as the active component of activity-dependent neuroprotective protein (ADNP), completely annihilated the adverse effects of A53T on mitochondrial dynamics. Our results reveal that A53T α-synuclein (oligomers or aggregates) leads to the inhibition of mitochondrial trafficking, which can be rescued by NAP, suggesting the involvement of microtubule disruption in the pathophysiology of Parkinson's disease.
authors.affiliation: Department of Genetics and Evolutionary Biology, Institute for Biosciences, University of Sao Paulo, Sao Paulo, Brazil.|Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: T Q
authors.initials: TQ
authors.lastname: Melo
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: K C
authors.initials: KC
authors.lastname: van Zomeren
authors.affiliation: Department of Genetics and Evolutionary Biology, Institute for Biosciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: M F R
authors.initials: MF
authors.lastname: Ferrari
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: H W G M
authors.initials: HW
authors.lastname: Boddeke
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands. j.c.v.m.copray@umcg.nl.
authors.forename: J C V M
authors.identifier: 0000-0003-2627-2082
authors.initials: JC
authors.lastname: Copray
mesh_terms: D000409:Alanine / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007734:Kymography; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics* / Q000473:pathology; D009447:Neuroblastoma / Q000473:pathology / Q000648:ultrastructure; D009842:Oligopeptides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013912:Threonine / Q000235:genetics; D014162:Transfection; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D008164:Luminescent Proteins; D008869:Microtubule-Associated Proteins; D009842:Oligopeptides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051844:alpha-Synuclein; D013912:Threonine; C425904:davunetide; D000409:Alanine
keywords: Microtubule; Mitochondria dysfunction; Mitochondrial trafficking; Neurodegeneration; Parkinson; Reactive oxygen species; SHSY5Y; α-Synuclein