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Hum Mol Genet. 2017 Dec 15;26(24):4906-4915. doi: 10.1093/hmg/ddx371.

Comparison of the in vivo induction and transmission of α-synuclein pathology by mutant α-synuclein fibril seeds in transgenic mice.

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Center for Translational Research in Neurodegenerative Disease.
Department of Neuroscience.
McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA.


Parkinson's disease (PD) is one of many neurodegenerative diseases termed synucleinopathies, neuropathologically defined by inclusions containing aggregated α-synuclein (αS). αS gene (SNCA) mutations can directly cause autosomal dominant PD. In vitro studies demonstrated that SNCA missense mutations may either enhance or diminish αS aggregation but cross-seeding of mutant and wild-type αS proteins appear to reduce aggregation efficiency. Here, we extended these studies by assessing the effects of seeded αS aggregation in αS transgenic mice through intracerebral or peripheral injection of various mutant αS fibrils. We observed modestly decreased time to paralysis in mice transgenic for human A53T αS (line M83) intramuscularly injected with H50Q, G51D or A53E αS fibrils relative to wild-type αS fibrils. Conversely, E46K αS fibril seeding was significantly delayed and less efficient in the same experimental paradigm. However, the amount and distribution of αS inclusions in the central nervous system were similar for all αS fibril muscle injected mice that developed paralysis. Mice transgenic for human αS (line M20) injected in the hippocampus with wild-type, H50Q, G51D or A53E αS fibrils displayed induction of αS inclusion pathology that increased and spread over time. By comparison, induction of αS aggregation following the intrahippocampal injection of E46K αS fibrils in M20 mice was much less efficient. These findings show that H50Q, G51D or A53E can efficiently cross-seed and induce αS pathology in vivo. In contrast, E46K αS fibrils are intrinsically inefficient at seeding αS inclusion pathology. Consistent with previous in vitro studies, E46K αS polymers are likely distinct aggregated conformers that may represent a unique prion-like strain of αS.

[Available on 2018-12-15]
[Indexed for MEDLINE]

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