@article{3175007,
    title = "Defective synaptic connectivity and axonal neuropathology in a human
iPSC-based model of familial Parkinson's disease",
    author = "Kouroupi, Georgia and Taoufik, Era and Vlachos, Ioannis S. and Tsioras, and Konstantinos and Antoniou, Nasia and Papastefanaki, Florentia and and Chroni-Tzartou, Dafni and Wrasidlo, Wolfgang and Bohl, Delphine and and Stellas, Dimitris and Politis, Panagiotis K. and Vekrellis, Kostas and and Papadimitriou, Dimitra and Stefanis, Leonidas and Bregestovski, Piotr and and Hatzigeorgiou, Artemis G. and Masliah, Eliezer and Matsas, Rebecca",
    journal = "PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA",
    year = "2017",
    volume = "114",
    number = "18",
    pages = "E3679-E3688",
    publisher = "NATL ACAD SCIENCES",
    doi = "10.1073/pnas.1617259114",
    keywords = "alpha-synuclein; axonal degeneration; dystrophic neurites; Parkinson's
disease; small molecules",
    abstract = "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."
}