Aggregated α-Synuclein Increases SOD1 Oligomerization in a Mouse Model of Amyotrophic Lateral Sclerosis.
Aggregation of misfolded disease-related proteins is a hallmark of neurodegenerative diseases. Aggregate propagation accompanying disease progression has been demonstrated for different proteins (eg, for α-synuclein). Additional evidence supports aggregate cross-seeding activity for α-synuclein. For mutated superoxide dismutase 1 (SOD1), which causes familial amyotrophic lateral sclerosis (ALS), self-propagation of aggregation and cell-to-cell transmission have been demonstrated in vitro. However, there is a prominent lack of in vivo data concerning aggregation and cross-aggregation processes of SOD1. We analyzed the effect of α-synuclein and SOD1 seeds in cell culture using protein fragment complementation assay and intracerebral injection of α-synuclein and SOD1 seeds into SOD1(G93A) transgenic ALS mice. Survival of injected mice was determined, and SOD1 aggregates in the facial nuclei were quantified during disease course. We found that α-synuclein preformed fibrils increased the oligomerization rate of SOD1 in vivo and in vitro, whereas aggregated SOD1 did not exert any effect in both experimental setups. Notably, survival of ALS mice was not changed after inoculation of preformed fibrils. We conclude that misfolded α-synuclein can increase SOD1 aggregation and suppose that α-synuclein seeds are transported from the temporal cortex to the facial nuclei. However, unlike other proteins, the further enhancement of a self-aggregation process by additional SOD1 could not be confirmed in our models.
Department of Neurology, University of Ulm, Ulm, Germany.
Yvonne
Y
Koch
Department of Neurology, University of Ulm, Ulm, Germany.
Anika M
AM
Helferich
Department of Neurology, University of Ulm, Ulm, Germany.
Petra
P
Steinacker
Department of Neurology, University of Ulm, Ulm, Germany.
Patrick
P
Oeckl
Central Facility for Electron Microscopy, University of Ulm, Ulm, Germany.
Paul
P
Walther
Department of Neurology, University of Ulm, Ulm, Germany.
Jochen H
JH
Weishaupt
Department of Neurology, University of Ulm, Ulm, Germany.
Karin M
KM
Danzer
Department of Neurology, University of Ulm, Ulm, Germany. Electronic address: markus.otto@uni-ulm.de.
Markus
M
Otto
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D000072105:Superoxide Dismutase-1 / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
D051844:alpha-Synuclein; C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1