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Proc Natl Acad Sci U S A. 2017 Apr 11;114(15):E3139-E3148. doi: 10.1073/pnas.1701465114. Epub 2017 Mar 27.

Transfer of pathogenic and nonpathogenic cytosolic proteins between spinal cord motor neurons in vivo in chimeric mice.

Author information

1
Interdepartmental Program in Neuroscience, Yale University School of Medicine, New Haven, CT 06510.
2
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510.
3
Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06510.
4
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510; arthur.horwich@yale.edu.
5
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.

Abstract

Recent studies have reported spread of pathogenic proteins in the mammalian nervous system, but whether nonpathogenic ones spread is unknown. We initially investigated whether spread of a mutant amyotrophic lateral sclerosis-associated cytosolic superoxide dismutase 1 (SOD1) protein between motor neurons could be detected in intact chimeric mice. Eight-cell embryos from G85R SOD1YFP and G85R SOD1CFP mice were aggregated, and spinal cords of adult chimeric progeny were examined for motor neurons with cytosolic double fluorescence. By 3 mo of age, we observed extensive double fluorescence, including in amyotrophic lateral sclerosis-affected cranial nerve motor nuclei but not in the relatively spared extraocular nuclei. Chimeras of nonpathogenic wtSOD1YFP and G85R SOD1CFP also exhibited double fluorescence. In a third chimera, mitochondrial mCherry did not transfer to G85R SOD1YFP motor neurons, suggesting that neither RNA nor organelles transfer, but mito-mCherry neurons received G85R SOD1YFP. In a chimera of ChAT promoter-EGFP and mito-mCherry, EGFP efficiently transferred to mito-mCherry+ cells. Thus, nonpathogenic cytosolic proteins appear capable of transfer. During study of both the SOD1FP and EGFP chimeras, we observed fluorescence also in small cells neighboring the motor neurons, identified as mature gray matter oligodendrocytes. Double fluorescence in the G85R SOD1FP chimera and observation of the temporal development of fluorescence first in motor neurons and then in these oligodendrocytes suggest that they may be mediators of transfer of cytosolic proteins between motor neurons.

KEYWORDS:

ALS; SOD1; aggregates; cranial nerves; oligodendrocytes

PMID:
28348221
PMCID:
PMC5393223
DOI:
10.1073/pnas.1701465114
[Indexed for MEDLINE]
Free PMC Article

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