MSc Exit Seminar – Andrea Bevan (Peever Lab)

REM sleep behaviour disorder (RBD) is characterized by excessive muscle twitches and a lack of muscle atonia during REM sleep. Alarmingly, 80 – 90% of RBD cases convert into synucleinopathies within 10 – 15 years. Synucleinopathies are characterized by α-synuclein (αSyn) aggregates that cause neuronal dysfunction and neurodegeneration. RBD is associated with the presence of αSyn aggregates and neurodegeneration in the brain areas that generate REM sleep muscle atonia, including the sublaterodorsal tegmental nucleus (SLD) and the ventromedial medulla (vmM). Disrupting the function of glutamatergic SLD neurons and GABA/glycinergic vmM neurons causes an RBD-like behavioural phenotype. This suggests that the same neuropathological mechanisms that underly synucleinopathy may cause RBD by disrupting the function of these atonia generating nuclei. To test this theory, aCre​recombinase-dependent AAV vector along with Cre-driver mousselines were used to overexpress αSyn selectively in glutamatergic SLD cells and GABA/glycinergic vmM cells to determine if this can induce αSyn aggregation and neurodegeneration in these REM sleep atonia generating sub-populations. I found that αSyn overexpression inglutamatergic SLD neurons and GABA/glycinergic vmM neurons caused αSyn aggregation. Importantly, αSyn pathology in GABA/glycinergic vmM neurons induced neuronal loss in this area. However, αSyn pathology in glutamatergic SLD cells did not cause neuronal loss at the time point that cell counting was performed. This project has provided an animal model that successfully recapitulates key neuropathological features of RBD preceding synucleinopathy and provides a means to further study the degenerative processes induced by αSyn pathology in the REM sleep atonia generating nuclei.