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

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 (2018)

Publication Language: English

Publication Type: Journal article

Publication year: 2018

Journal

Proceedings of the National Academy of Sciences of the United States of America National Academy of Sciences

Book Volume: 115

Pages Range: 7813-7818

Journal Issue: 30

DOI: 10.1073/pnas.1713129115

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.

Authors with CRIS profile

Iryna Prots Professur für Stammzell-Modelle seltener neuraler Erkrankungen Janina Grosch Professur für Molekulare Neurologie Katrin Simmnacher Professur für Stammzell-Modelle seltener neuraler Erkrankungen Steven Havlicek Department of Molecular Neurology André Wiesmann da Silva Reis Lehrstuhl für Humangenetik Ursula Schlötzer-Schrehardt Medizinische Fakultät Wei Xiang Lehrstuhl für Biochemie und Molekulare Medizin Jürgen Winkler Professur für Molekulare Neurologie Beate Winner Professur für Stammzell-Modelle seltener neuraler Erkrankungen

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Involved external institutions

University of California, San Diego US United States (USA) (US)

How to cite

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 of the United States of America, 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 of the United States of America 115.30 (2018): 7813-7818.

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