α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies

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Details zur Publikation

Autor(en): Prots I, Grosch J, Brazdis RM, Simmnacher K, Veber V, Havlicek S, Hannappel C, Krach F, Krumbiegel M, Schuetz O, Reis A, Wrasidlo W, Galasko DR, Groemer TW, Masliah E, Schlötzer-Schrehardt U, Xiang W, Winkler J, Winner B
Zeitschrift: Proceedings of the National Academy of Sciences
Jahr der Veröffentlichung: 2018
Band: 115
Heftnummer: 30
Seitenbereich: 7813-7818
ISSN: 0027-8424
eISSN: 1091-6490


Abstract

α-Synuclein (α-Syn) aggregation, proceeding from oligomers to fibrils, is one central hallmark of neurodegeneration in synucleinopathies. α-Syn oligomers are toxic by triggering neurodegenerative processes in in vitro and in vivo models. However, the precise contribution of α-Syn oligomers to neurite pathology in human neurons and the underlying mechanisms remain unclear. Here, we demonstrate the formation of oligomeric α-Syn intermediates and reduced axonal mitochondrial transport in human neurons derived from induced pluripotent stem cells (iPSC) from a Parkinson's disease patient carrying an α-Syn gene duplication. We further show that increased levels of α-Syn oligomers disrupt axonal integrity in human neurons. We apply an α-Syn oligomerization model by expressing α-Syn oligomer-forming mutants (E46K and E57K) and wild-type α-Syn in human iPSC-derived neurons. Pronounced α-Syn oligomerization led to impaired anterograde axonal transport of mitochondria, which can be restored by the inhibition of α-Syn oligomer formation. Furthermore, α-Syn oligomers were associated with a subcellular relocation of transport-regulating proteins Miro1, KLC1, and Tau as well as reduced ATP levels, underlying axonal transport deficits. Consequently, reduced axonal density and structural synaptic degeneration were observed in human neurons in the presence of high levels of α-Syn oligomers. Together, increased dosage of α-Syn resulting in α-Syn oligomerization causes axonal transport disruption and energy deficits, leading to synapse loss in human neurons. This study identifies α-Syn oligomers as the critical species triggering early axonal dysfunction in synucleinopathies.


FAU-Autoren / FAU-Herausgeber

Grosch, Janina
Professur für Molekulare Neurologie
Havlicek, Steven
Molekular-Neurologische Abteilung in der Neurologischen Klinik
Prots, Iryna Dr.
Professur für Stammzell-Modelle seltener neuraler Erkrankungen
Schlötzer-Schrehardt, Ursula apl. Prof. Dr.
Medizinische Fakultät
Simmnacher, Katrin
Professur für Stammzell-Modelle seltener neuraler Erkrankungen
Winkler, Jürgen Prof. Dr.
Molekular-Neurologische Abteilung in der Neurologischen Klinik
Winner, Beate Prof. Dr.
Professur für Stammzell-Modelle seltener neuraler Erkrankungen
Xiang, Wei PD Dr.
Lehrstuhl für Biochemie und Molekulare Medizin


Autor(en) der externen Einrichtung(en)
University of California, San Diego


Zitierweisen

APA:
Prots, I., Grosch, J., Brazdis, R.-M., Simmnacher, K., Veber, V., Havlicek, S.,... Winner, B. (2018). α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies. Proceedings of the National Academy of Sciences, 115(30), 7813-7818. https://dx.doi.org/10.1073/pnas.1713129115

MLA:
Prots, Iryna, et al. "α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies." Proceedings of the National Academy of Sciences 115.30 (2018): 7813-7818.

BibTeX: 

Zuletzt aktualisiert 2018-10-10 um 12:53