RT Journal Article
SR Electronic
T1 PINK1 Regulates Dopamine and Lipids at Mitochondria to Maintain Synapses and Neuronal Function
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 814343
DO 10.1101/814343
A1 Christine Bus
A1 Sven Geisler
A1 Marita Feldkaemper
A1 Hector Flores-Romero
A1 Anna Schaedler
A1 Katharina Zittlau
A1 Maria Zarani
A1 Betül Uysal
A1 Nicolas Casadei
A1 Petra Fallier-Becker
A1 Lisa Schwarz
A1 Jos F. Brouwers
A1 Henner Koch
A1 Aslihan Ugun-Klusek
A1 Klaudia Maruszczak
A1 Daniela M. Vogt Weisenhorn
A1 Wolfgang Wurst
A1 Benjamin Schmidt
A1 Gerard Martens
A1 Britta Brügger
A1 Doron Rapaport
A1 Ana Garcia
A1 Boris Macek
A1 Rejko Krüger
A1 Thomas Gasser
A1 Philipp Kahle
A1 Julia C. Fitzgerald
YR 2019
UL http://biorxiv.org/content/early/2019/10/22/814343.abstract
AB Mitochondrial dysfunction contributes to the pathogenesis of Parkinson’s disease but it is not clear why inherent mitochondrial defects lead specifically to the death of dopaminergic neurons of the mid brain. PINK1 is mitochondrial kinase and PINK1 mutations cause early onset Parkinson’s disease.We found that in neuronal progenitors, PINK1 regulates mitochondrial morphology, mitochondrial contact to the endoplasmic reticulum (ER) and the phosphorylation of Miro1. A compensatory metabolic shift towards lipid synthesis provides mitochondria with the components needed for membrane renewal and oxidative phosphorylation, maintaining the mitochondrial network once mature.Cholesterol is increased by loss of PINK1, promoting overall membrane rigidity. This alters the distribution of phosphorylated DAT at synapses and impairs dopamine uptake. PINK1 is required for the phosphorylation of tyrosine hydroxylase at Ser19, dopamine and calcium homeostasis and dopaminergic pacemaking.We suggest a novel mechanism for PINK1 pathogenicity in Parkinson’s disease in addition to but not exclusive of mitophagy. We also provide a basis for potential therapeutics by showing that low doses of the cholesterol depleting drug ß-cyclodextrin reverse PINK1-specific phenotypes.