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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2016

Open Access 01-12-2016 | Short report

Transmission of α-synucleinopathy from olfactory structures deep into the temporal lobe

Authors: Daniel M. Mason, Negin Nouraei, Deepti B. Pant, Kristin M. Miner, Daniel F. Hutchison, Kelvin C. Luk, John F. Stolz, Rehana K. Leak

Published in: Molecular Neurodegeneration | Issue 1/2016

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Abstract

Background

α-synucleinopathy emerges quite early in olfactory structures such as the olfactory bulb and anterior olfactory nucleus (OB/AON) in Parkinson's disease. This may contribute to smell impairments years before the commencement of motor symptoms. We tested whether α-synucleinopathy can spread from the OB/AON to regions of the limbic telencephalon that harbor connections with olfactory structures.

Findings

α-synuclein fibrils were infused into the OB/AON. Inclusions containing pathologically phosphorylated α-synuclein (pSer129) were observed three months later in the piriform and entorhinal cortices, amygdala, and hippocampal formation. The retrograde tract-tracer FluoroGold confirmed the existence of first-order afferents at these sites. Some sites harbored FluoroGold+ neurons but no inclusions, suggestive of selective vulnerabilities. Multiple areas close to the injection site but not connected with the OB/AON remained free of inclusions, suggesting a lack of widespread uptake of fibrils from interstitial diffusion. Two independent pSer129 antibodies revealed the same labeling patterns and preadsorption control experiments confirmed a loss of pSer129 staining. Dense total α-synuclein (but not pSer129) staining was apparent in the OB/AON 1.5 h following fibril infusions, suggesting that pSer129+ staining did not reflect exogenously infused material. Waterbath sonication of fibrils for 1 h improved α-synucleinopathy transmission relative to 1 min-long probe sonication. Electron microscopy revealed that longer sonication durations reduced fibril size. The Thioflavin stain labeled cells at the infusion site and some, but not all inclusions contained ubiquitin. Three-dimensional confocal analyses revealed that many inclusions ensconced NeuN+ neuronal nuclei. Young and aged mice exhibited similar topographical spread of α-synucleinopathy.

Conclusions

1) α-synucleinopathy in this model is transmitted through some, but not all neuroanatomical connections, 2) pathology is largely confined to first-order afferent sites at three months and this is most parsimoniously explained by retrograde transport, and 3) transmission in aged animals is largely similar to that in young control animals at three months post-infusion.
Appendix
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Metadata
Title
Transmission of α-synucleinopathy from olfactory structures deep into the temporal lobe
Authors
Daniel M. Mason
Negin Nouraei
Deepti B. Pant
Kristin M. Miner
Daniel F. Hutchison
Kelvin C. Luk
John F. Stolz
Rehana K. Leak
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2016
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-016-0113-4

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