Objective: In our present study, we developed a new mouse model to study the time dependent effects of cellular A53T-α-synuclein overexpression in the locus coeruleus, regarding the toxicity caused by α-synuclein accumulation, the alteration in electrophysiological properties and noradrenergic cell loss.

Background: Dysfunction of the noradrenergic locus coeruleus (LC) is an early hallmark of Parkinson’s disease (PD). The extensive loss of noradrenergic LC neurons in PD is responsible for a large amount of non-motor symptoms that occur in early stages of the disease. However, the mechanisms that render LC neurons prone to α-synuclein accumulation and neurodegeneration are still unclear.

Methods: Serotype 1/2 recombinant adeno-associated viral vectors (rAAV) carrying the genome for A53T-α-synuclein or luciferase were unilaterally injected in the right LC of C57Bl/6 wildtype mice to induce continuous protein overexpression. At 1, 3, 6 and 9 weeks post injection, eight animals overexpressing either A53T or luciferase were sacrificed for immunohistochemical analysis. In addition, four animals per group and timepoint were used to study the biophysical characteristics of LC neurons by patch-clamp recordings in acute brainstem slices.

Results: We show, that targeted overexpression of A53T-α-synuclein in the LC of wildtype mice caused progressive α-synuclein accumulation and significant loss of noradrenergic LC neurons in the injected side in a time dependent manner, starting 3 weeks post-injection. Aggregated forms of α-synuclein were confirmed by Proteinase K resistance and Ser129 phosphorylation. Furthermore, overexpression of α-synuclein led to a progressive increase of astro- and microglia density in the injected LC region. In our model, neurodegeneration of LC cells was associated with significant changes of their electrophysiological properties. Time dependently, A53T-α-synuclein overexpression induced alterations in action potential shape and an acceleration of the pacemaking frequency.

Conclusions: Our data indicate that overexpressed A53T-α-synuclein accumulates steadily in LC neurons, while simultaneously induces neuroinflammation and major changes in electrophysiological properties, which might be responsible for the observed cell death of LC neurons.

References: Disclaimer: L.A. Matschke and WH. Chiu have received a grant by the intramural research fund of the Rhön-AG. B. Lee is a DAAD fellow. W.H. Oertel is supported by the Charitable Hertie Foundation, Frankfurt/Main, Germany.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/targeted-overexpression-of-a53t-alpha-synuclein-induces-progressive-neurodegeneration-and-electrophysiological-changes-of-noradrenergic-locus-coeruleus-neurons-a-preclinical-model-of-parkins/