Rapid dissemination of alpha-synuclein seeds through neural circuits in an in-vivo prion-like seeding experiment

Ayami Okuzumi, Masaru Kurosawa, Taku Hatano, Masashi Takanashi, Shuuko Nojiri, Takeshi Fukuhara, Tomoyuki Yamanaka, Haruko Miyazaki, Saki Yoshinaga, Yoshiaki Furukawa, Tomomi Shimogori, Nobutaka Hattori, Nobuyuki Nukina

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Accumulating evidence suggests that the lesions of Parkinson's disease (PD) expand due to transneuronal spreading of fibrils composed of misfolded alpha-synuclein (a-syn), over the course of 5-10 years. However, the precise mechanisms and the processes underlying the spread of these fibril seeds have not been clarified in vivo. Here, we investigated the speed of a-syn transmission, which has not been a focus of previous a-syn transmission experiments, and whether a-syn pathologies spread in a neural circuit-dependent manner in the mouse brain. We injected a-syn preformed fibrils (PFFs), which are seeds for the propagation of a-syn deposits, either before or after callosotomy, to disconnect bilateral hemispheric connections. In mice that underwent callosotomy before the injection, the propagation of a-syn pathology to the contralateral hemisphere was clearly reduced. In contrast, mice that underwent callosotomy 24 h after a-syn PFFs injection showed a-syn pathology similar to that seen in mice without callosotomy. These results suggest that a-syn seeds are rapidly disseminated through neuronal circuits immediately after seed injection, in a prion-like seeding experiment in vivo, although it is believed that clinical a-syn pathologies take years to spread throughout the brain. In addition, we found that botulinum toxin B blocked the transsynaptic transmission of a-syn seeds by specifically inactivating the synaptic vesicle fusion machinery. This study offers a novel concept regarding a-syn propagation, based on the Braak hypothesis, and also cautions that experimental transmission systems may be examining a unique type of transmission, which differs from the clinical disease state.

Original languageEnglish
Number of pages1
JournalActa Neuropathologica Communications
Volume6
Issue number1
DOIs
Publication statusPublished - 2018 Sep 19

Keywords

  • A-syn
  • Callosotomy
  • Propagation
  • Rapid dissemination

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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    Okuzumi, A., Kurosawa, M., Hatano, T., Takanashi, M., Nojiri, S., Fukuhara, T., Yamanaka, T., Miyazaki, H., Yoshinaga, S., Furukawa, Y., Shimogori, T., Hattori, N., & Nukina, N. (2018). Rapid dissemination of alpha-synuclein seeds through neural circuits in an in-vivo prion-like seeding experiment. Acta Neuropathologica Communications, 6(1). https://doi.org/10.1186/s40478-018-0587-0