Luke, R.; Yoo, H. S.; McKenna, D.; Bevan, A.; Durso, C.; Dugan, B. J.; Liang, Y.; Amanirad, B.; Steltz, J. A.; Zhang, B.; Yearwood, A.; Lourie, J.; Lee, P. H.; Fraigne, J. J.; Peever, J. H.; Luk, K. C.

REM sleep behaviour disorder (RBD) is a prodromal manifestation of -synucleinopathies such as Parkinson's disease. Evidence suggests that degeneration of REM sleep regulating neurons in the sublaterodorsal tegmental nucleus (SLD) could give rise to RBD, yet the specific cellular populations involved and their contribution to synucleinopathy progression remain unclear. Here, we investigated the role of defined SLD cell types in RBD pathogenesis. Using viral vector and fibril-based models of -synucleinopathy, we show that -synuclein pathology in SLD neurons triggers RBD in mice. Notably, glutamatergic SLD neurons are selectively vulnerable to synucleinopathy and the loss of these cells correlates with RBD severity. Propagation of synucleinopathy from the SLD to midbrain and forebrain structures leads to the emergence of neurological deficits associated with Parkinson's disease. These findings establish that SLD neurons are critical substrates for RBD and provide insight into the cellular mechanisms at play in the early stages of synucleinopathies.