Comparative analyses of the in vivo induction and transmission of α-synuclein pathology in transgenic mice by MSA brain lysate and recombinant α-synuclein fibrils

Acta Neuropathologica Communications

Jorge A. Trejo-Lopez¹  Amanda N. Sacino²  Cara Riffe²  Jess-Karan S. Dhillon²  Yona Levites²  Benoit I. Giasson³  David R. Borchelt³  Anthony Y. Yachnis⁴ 

[1] 0000 0004 1936 8091, grid.15276.37, Center for Translational Research in Neurodegenerative Disease, University of Florida, 32610, Gainesville, FL, USA;0000 0004 1936 8091, grid.15276.37, Department of Pathology, University of Florida, 32610, Gainesville, FL, USA;0000 0004 1936 8091, grid.15276.37, Department of Neuroscience, University of Florida, 32610, Gainesville, FL, USA;0000 0004 1936 8091, grid.15276.37, Center for Translational Research in Neurodegenerative Disease, University of Florida, 32610, Gainesville, FL, USA;0000 0004 1936 8091, grid.15276.37, Department of Neuroscience, University of Florida, 32610, Gainesville, FL, USA;0000 0004 1936 8091, grid.15276.37, Center for Translational Research in Neurodegenerative Disease, University of Florida, 32610, Gainesville, FL, USA;0000 0004 1936 8091, grid.15276.37, McKnight Brain Institute, University of Florida, 32610, Gainesville, FL, USA;0000 0004 1936 8091, grid.15276.37, Department of Pathology, University of Florida, 32610, Gainesville, FL, USA;

关键词: α-Synuclein;    Multiple system atrophy;    Prion;    Seeding;    Transgenic;   

DOI  :  10.1186/s40478-019-0733-3

来源: publisher

【 摘 要 】

α-synuclein (αS) is the major component of several types of brain pathological inclusions that define neurodegenerative diseases termed synucleinopathies. Central nervous system (CNS) inoculation studies using either in vitro polymerized αS fibrils or in vivo derived lysates containing αS aggregates to induce the progressive spread of αS inclusion pathology in animal disease models have supported the notion that αS mediated progressive neurodegeneration can occur by a prion-like mechanism. We have previously shown that neonatal brain inoculation with preformed αS fibrils in hemizygous M20+/− transgenic mice expressing wild type human αS and to a lesser extent in non-transgenic mice can result in a concentration-dependent progressive induction of CNS αS pathology. Recent studies using brain lysates from patients with multiple system atrophy (MSA), characterized by αS inclusion pathology in oligodendrocytes, indicate that these may be uniquely potent at inducing αS pathology with prion-like strain specificity. We demonstrate here that brain lysates from MSA patients, but not control individuals, can induce αS pathology following neonatal brain inoculation in transgenic mice expressing A53T human αS (M83 line), but not in transgenic expressing wild type human αS (M20 line) or non-transgenic mice within the timeframe of the study design. Further, we show that neuroanatomical and immunohistochemical properties of the pathology induced by MSA brain lysates is very similar to what is produced by the neonatal brain injection of preformed human αS fibrils in hemizygous M83+/− transgenic mice. Collectively, these findings reinforce the idea that the intrinsic traits of the M83 mouse model dominates over any putative prion-like strain properties of MSA αS seeds that can induce pathology.

【 授权许可】

CC BY