TY - JOUR
TI - Defective synaptic connectivity and axonal neuropathology in a human
iPSC-based model of familial Parkinson's disease
AU - Kouroupi, Georgia
AU - Taoufik, Era
AU - Vlachos, Ioannis S.
AU - Tsioras,
AU - Konstantinos
AU - Antoniou, Nasia
AU - Papastefanaki, Florentia and
AU - Chroni-Tzartou, Dafni
AU - Wrasidlo, Wolfgang
AU - Bohl, Delphine and
AU - Stellas, Dimitris
AU - Politis, Panagiotis K.
AU - Vekrellis, Kostas and
AU - Papadimitriou, Dimitra
AU - Stefanis, Leonidas
AU - Bregestovski, Piotr
AU - and Hatzigeorgiou, Artemis G.
AU - Masliah, Eliezer
AU - Matsas, Rebecca
JO - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
PY - 2017
VL - 114
TODO - 18
SP - E3679-E3688
PB - NATL ACAD SCIENCES
SN - null
TODO - 10.1073/pnas.1617259114
TODO - alpha-synuclein; axonal degeneration; dystrophic neurites; Parkinson's
disease; small molecules
TODO - alpha-Synuclein (alpha Syn) is the major gene linked to sporadic
Parkinson's disease (PD), whereas the G209A (p.A53T) alpha Syn mutation
causes a familial form of PD characterized by early onset and a
generally severe phenotype, including nonmotor manifestations. Here we
generated de novo induced pluripotent stem cells (iPSCs) from patients
harboring the p.A53T mutation and developed a robust model that captures
PD pathogenic processes under basal conditions. iPSC-derived mutant
neurons displayed novel disease-relevant phenotypes, including protein
aggregation, compromised neuritic outgrowth, and contorted or fragmented
axons with swollen varicosities containing alpha Syn and Tau. The
identified neuropathological features closely resembled those in brains
of p.A53T patients. Small molecules targeting alpha Syn reverted the
degenerative phenotype under both basal and induced stress conditions,
indicating a treatment strategy for PD and other synucleinopathies.
Furthermore, mutant neurons showed disrupted synaptic connectivity and
widespread transcriptional alterations in genes involved in synaptic
signaling, a number of which have been previously linked to mental
disorders, raising intriguing implications for potentially converging
disease mechanisms.
ER -