Elsevier

Neurobiology of Aging

Volume 33, Issue 9, September 2012, Pages 2225-2228
Neurobiology of Aging

Rapid communication
Prion-like acceleration of a synucleinopathy in a transgenic mouse model

https://doi.org/10.1016/j.neurobiolaging.2011.06.022Get rights and content

Abstract

Our aim in this study was to investigate experimentally the possible in vivo transmission of a synucleinopathy, using a transgenic mouse model (TgM83) expressing the human A53T mutated α-synuclein. Brain homogenates from old TgM83 mice showing motor clinical signs due to the synucleinopathy and containing insoluble and phosphorylated (pSer129) α-synuclein were intracerebrally inoculated in young TgM83 mice. This triggered an early onset of characteristic motor clinical signs, compared with uninoculated TgM83 mice or to mice inoculated with a brain homogenate from a young, healthy TgM83 mouse. This early disease was associated with insoluble α-synuclein phosphorylated on Ser129, as already identified in old and sick uninoculated TgM83 transgenic mice. Although the molecular mechanisms remain to be determined, acceleration of the pathology following inoculation of mice expressing human mutated α-synuclein with tissues from mice affected by the synucleinopathy, could be consistent with “prion-like” propagation of the disease.

Introduction

Pathological accumulation of misfolded neuronal proteins, leading to synaptic dysfunction and cell death, is assumed to play a central role in the pathogenesis of many neurodegenerative disorders. Although synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB), are not infectious pathologies, recent studies suggested the existence of common mechanisms underlying the propagation of α-synuclein (α-syn) and prion alterations (Angot et al., 2010). Here, we investigated the potential in vivo transmission of a synucleinopathy, using a transgenic mouse model (TgM83) expressing the human A53T mutated α-synuclein (Giasson et al., 2002).

Section snippets

Animal bioassays

Homozygous TgM83 mice (7–9 weeks old) were inoculated intracerebrally with 20 μL of 1% (wt/vol in glucose 5%) homogenates obtained from half of the brain of old (12–18 months) TgM83 mice euthanized following the development of clinical signs due to the α-syn pathology. Controls included: (1) uninoculated TgM83 mice, (2) TgM83 mice inoculated with a brain homogenate from a 2-month-old healthy TgM83 mouse, and (3) C57Bl/6S mice, presenting a deletion of the α-syn locus (Harlan, Gannat, France) (

Results

A transgenic mouse model of synucleinopathy was used (TgM83) (Giasson et al., 2002), in which mice develop a severe motor impairment associated with detection of insoluble pSer129 α-syn only at a late stage of the disease (Mougenot et al., 2011, Waxman and Giasson, 2008).

No statistically significant difference was found (p = 0.273) between the survival times of TgM83 mice uninoculated (median 435 days old) or inoculated with a brain homogenate from a 2-month-old healthy TgM83 mouse (median 359

Discussion

The common feature of synucleinopathies is the accumulation of intracellular aggregates of α-syn that spread throughout the brain. Possible similarities in propagation of the α-syn pathology with that of prions have been highlighted in recent studies (Angot et al., 2010). We therefore adopted the procedures routinely performed to transmit prion diseases in mice, using i.c. inoculation of brain homogenates of affected animals, in a transgenic mouse model of human synucleinopathy (TgM83) (Giasson

Disclosure statement

The authors declare no conflicts of interest.

The animals were cared for and housed in approved experimental facilities (n°A69387081), in accordance with the EC Directive 86/609/EEC and with the Regional Committee for Ethical Experimentation on Animals (protocol n°98).

Acknowledgements

We are grateful to D. Bétemps, J.-M. Bridon, M. Leboidre, and to the staff of Plate-forme d'expérimentation animale Anses-Lyon for their contribution to the study. A.-L.M. was supported by a training grant (CIFRE 2006/1050) from the Association Nationale pour la Recherche et la Technologie.

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