TY - JOUR
T1 - Rapid dissemination of alpha-synuclein seeds through neural circuits in an in-vivo prion-like seeding experiment
AU - Okuzumi, Ayami
AU - Kurosawa, Masaru
AU - Hatano, Taku
AU - Takanashi, Masashi
AU - Nojiri, Shuuko
AU - Fukuhara, Takeshi
AU - Yamanaka, Tomoyuki
AU - Miyazaki, Haruko
AU - Yoshinaga, Saki
AU - Furukawa, Yoshiaki
AU - Shimogori, Tomomi
AU - Hattori, Nobutaka
AU - Nukina, Nobuyuki
N1 - Funding Information:
This research is supported by the Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and Development, AMED under Grant Number JP18dm0107140 to N.N., from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan to N.N. (17H01564), T.H.(25461290), by a Grant-in-Aid for Research on Measures for Ataxic Diseases to N.N, and by Grants-in Aid from the Research Committee of CNS Degenerative Disease, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labour and Welfare Sciences Research Grants to N.H. from the Ministry of Health, Labour and Welfare,Japan. We thank Itsuko Yamamoto for mice maintenance and thank Akiko Sumi for Immunostaining for human samples.
PY - 2018/9/19
Y1 - 2018/9/19
N2 - 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.
AB - 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.
KW - A-syn
KW - Callosotomy
KW - Propagation
KW - Rapid dissemination
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U2 - 10.1186/s40478-018-0587-0
DO - 10.1186/s40478-018-0587-0
M3 - Article
C2 - 30231908
AN - SCOPUS:85059578934
SN - 2051-5960
VL - 6
SP - 96
JO - Acta neuropathologica communications
JF - Acta neuropathologica communications
IS - 1
ER -