Modeling Lewy pathology propagation in Parkinson's disease

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Summary

Lewy bodies (LBs) and Lewy neurites (LNs), comprised of alpha-synuclein (aSyn), are intraneuronal inclusions that characterize Parkinson's disease. Although the association between the extent of Lewy pathology and clinical symptoms is well established, how these proteinaceous deposits originate and target selectively vulnerable cell populations is unknown. Our knowledge of their role in PD pathogenesis is also limited. Here, we summarize recent findings demonstrating this pathology can be experimentally transmitted between animals by misfolded forms of aSyn that are capable of initiating and inducing LB and LN inclusion formation through a self-propagating mechanism reminiscent of prions. “Seeded” LBs and LNs in animal models also spread to multiple connected nuclei in a predictable pattern, recapitulating a phenomenon observed during human PD progression, leading to the dysfunction and degeneration of afflicted neurons. These models provide new perspectives on how this and other misfolded proteins may contribute to neurodegeneration in human disease.

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      To address this hypothesis, several groups have tested the seeding and prion-like spreading of pathological αsyn in vivo (Dehay and Fernagut, 2016; Dehay et al., 2016; Rey et al., 2018b). Intracerebral or peripheral injection of recombinant αsyn fibrils or αsyn aggregates derived from brain lysates from post-mortem patients with synucleinopathy can induce αsyn aggregation in both animals overexpressing αsyn and in wild type animals (Brundin and Melki, 2017; Dehay et al., 2016; Luk and Lee, 2014; Recasens et al., 2018; Rey et al., 2018b). Several previously published studies have focused on defining the development of abnormal αsyn inclusions following injections into the striatum or in the substantia nigra, which exhibit synucleinopathy only in advanced PD.

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