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

Proc Natl Acad Sci U S A. 2018 Jul 24;115(30):7813-7818. doi: 10.1073/pnas.1713129115. Epub 2018 Jul 10.

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.

Keywords: axonal transport; neurodegeneration; oligomers; synucleinopathies; α-synuclein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Axonal Transport*
  • Axons / metabolism*
  • Axons / pathology
  • Cell Line
  • Energy Metabolism / genetics
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Induced Pluripotent Stem Cells / pathology
  • Kinesins
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Models, Biological*
  • Mutation, Missense
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / pathology
  • Protein Multimerization*
  • alpha-Synuclein
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism
  • tau Proteins / genetics
  • tau Proteins / metabolism

Substances

  • KLC1 protein, human
  • MAPT protein, human
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • SNCA protein, human
  • alpha-Synuclein
  • tau Proteins
  • RHOT1 protein, human
  • Kinesins
  • rho GTP-Binding Proteins