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Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice.

Abstract

The accumulation of misfolded proteins is a fundamental pathogenic process in neurodegenerative diseases. However, the factors that trigger aggregation of α-Synuclein (α-Syn), the principal component of the intraneuronal inclusions known as Lewy bodies (LBs), and Lewy neurites (LNs), which characterize Parkinson's disease (PD) and dementia with LBs (DLB), are poorly understood. We show here that in young asymptomatic α-Syn transgenic (Tg) mice, intracerebral injections of brain homogenates derived from older Tg mice exhibiting α-Syn pathology accelerate both the formation of intracellular LB/LN-like inclusions and the onset of neurological symptoms in recipient animals. Pathological α-Syn propagated along major central nervous system (CNS) pathways to regions far beyond injection sites and reduced survival with a highly reproducible interval from injection to death in inoculated animals. Importantly, inoculation with α-Syn amyloid fibrils assembled from recombinant human α-Syn induced identical consequences. Furthermore, we show for the first time that synthetic α-Syn fibrils are wholly sufficient to initiate PD-like LBs/LNs and to transmit disease in vivo. Thus, our data point to a prion-like cascade in synucleinopathies whereby cell-cell transmission and propagation of misfolded α-Syn underlie the CNS spread of LBs/LNs. These findings open up new avenues for understanding the progression of PD and for developing novel therapeutics.

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    • Authors

    Luk KC, Kehm VM, Zhang B, O'Brien P, Trojanowski JQ, Lee VM

    Institution

    Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

    Source

    The Journal of experimental medicine 209:5 2012 May 7 pg 975-86

    MeSH

    Amyloid
    Animals
    Brain
    Humans
    Immunohistochemistry
    Injections
    Lewy Body Disease
    Male
    Mice
    Mice, Transgenic
    alpha-Synuclein

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22508839