Objective: To investigate whether in wild-type mice, inoculation of α-synuclein (aSyn) preformed fibrils (PFFs) into the sublaterodorsal tegmental nucleus (SLD), a core structure associated with REM sleep, would lead to either REM sleep behavior disorder (RBD) or subsequent parkinsonism-like phenotype.

Background: RBD is widely established as a highly predictive symptom of future alpha-synucleinopathy. The SLD plays a critical role in maintaining muscle atonia during REM sleep. Although the underlying mechanisms of RBD remain unknown, it is thought that RBD is caused by aSyn-mediated degeneration of the SLD neurons. Therefore, the development of a robust animal model that incorporates synucleinopathy and recapitulates RBD would offer a unique opportunity to study a prodromal phase of synucleinopathy.

Method: We stereotaxically injected recombinant wild-type mouse aSyn PFF into the SLD in B6C3F1/J mice. At predetermined time points, mice then underwent histopathological, electrophysiological, and behavioral analysis. Co-labeling using antibodies to phosphorylated (pS129) aSyn and common neurotransmitter markers was used to reveal neurons susceptible to pathology.

Results: By 1-month post-injection (MPI) with PFF, seeded pathological aSyn aggregates were detected within the SLD. Pathology was detected bilaterally in widespread areas both caudal and rostral to the SLD injection site and a few pathologies were detected in the substantia nigra pars compacta at 6 MPI. Using electrophysiology, we observed that mice spent a significantly greater proportion of REM sleep time twitching and twitched earlier during REM episodes than PBS-injected mice from 3 MPI. PFF-injected mice group also showed decreased grip strength, reduced total speed in open field test, and gait abnormalities in Catwalk analysis at 6 MPI. All pS129 aSyn pathologies were detected in the cholinergic neurons, but not in the noradrenergic, glutamatergic, or GABAergic neurons, within the SLD. Analyses of these and additional cohorts are ongoing.

Conclusion: We demonstrate that the SLD can serve as a portal for the early spread of synucleinopathy and that induction of aSyn pathology in this manner results in an RBD-like phenotype in mice. We anticipate this mouse model will be a useful tool for understanding prodromal disease mechanisms and studying disease-modifying treatment in synucleinopathy.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/alpha-synuclein-fibril-based-mouse-model-of-rem-sleep-behavior-disorder-as-a-prodrome-of-synucleinopathy/