title: Parkin mutations reduce the complexity of neuronal processes in iPSC-derived human neurons.
abstract: Parkinson's disease (PD) is characterized by the degeneration of nigral dopaminergic (DA) neurons and non-DA neurons in many parts of the brain. Mutations of parkin, an E3 ubiquitin ligase that strongly binds to microtubules, are the most frequent cause of recessively inherited PD. The lack of robust PD phenotype in parkin knockout mice suggests a unique vulnerability of human neurons to parkin mutations. Here, we show that the complexity of neuronal processes as measured by total neurite length, number of terminals, number of branch points, and Sholl analysis was greatly reduced in induced pluripotent stem cell (iPSC)-derived TH(+) or TH(-) neurons from PD patients with parkin mutations. Consistent with these, microtubule stability was significantly decreased by parkin mutations in iPSC-derived neurons. Overexpression of parkin, but not its PD-linked mutant nor green fluorescent protein, restored the complexity of neuronal processes and the stability of microtubules. Consistent with these, the microtubule-depolymerizing agent colchicine mimicked the effect of parkin mutations by decreasing neurite length and complexity in control neurons while the microtubule-stabilizing drug taxol mimicked the effect of parkin overexpression by enhancing the morphology of parkin-deficient neurons. The results suggest that parkin maintains the morphological complexity of human neurons by stabilizing microtubules.
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ren
authors.forename: Houbo
authors.initials: H
authors.lastname: Jiang
authors.forename: Zhixing
authors.initials: Z
authors.lastname: Hu
authors.forename: Kevin
authors.initials: K
authors.lastname: Fan
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Stephen
authors.initials: S
authors.lastname: Janoschka
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.forename: Shaoyu
authors.initials: S
authors.lastname: Ge
authors.forename: Jian
authors.initials: J
authors.lastname: Feng
mesh_terms: D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000201:enzymology / Q000502:physiology*; D009154:Mutation; D009474:Neurons / Q000201:enzymology / Q000502:physiology* / Q000648:ultrastructure; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D039904:Pluripotent Stem Cells / Q000201:enzymology / Q000473:pathology / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: Dopamine; Induced pluripotent stem cells; Microtubule; Parkin; Parkinson's disease