Περίληψη:
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.
Συγγραφείς:
Kouroupi, Georgia
Taoufik, Era
Vlachos, Ioannis S.
Tsioras,
Konstantinos
Antoniou, Nasia
Papastefanaki, Florentia and
Chroni-Tzartou, Dafni
Wrasidlo, Wolfgang
Bohl, Delphine and
Stellas, Dimitris
Politis, Panagiotis K.
Vekrellis, Kostas and
Papadimitriou, Dimitra
Stefanis, Leonidas
Bregestovski, Piotr
and Hatzigeorgiou, Artemis G.
Masliah, Eliezer
Matsas, Rebecca
