α-Synuclein Responses: Implications for Early Appearance of Sleep Disorders in Parkinson’s Disease

Abstract Sleep Disorders (SDs) precede motor symptoms of Parkinson’s disease (PD), suggesting an early effect of disease processes on sleep control neurons. PD processes involve rises in the protein, α-synuclein, which presents early on in a simple, monomeric form, but later in disease progression, a more complex fibril form appears. We hypothesize that monomeric α-synuclein has deleterious cellular actions on sleep control nuclei. We monitored cellular responses to identified monomeric and fibril α-synuclein in two sleep controlling nuclei, the laterodorsal tegmentum, and the pedunculopontine tegmentum, as well as the substantia nigra, a motor control nucleus which degenerates as a hallmark PD feature. We monitored differential cell death using a fluorescent-based assay following exposure to the simpler form of α-synuclein. In sleep control nuclei, both forms of intrinsic α-synuclein induced excitation, and increased intracellular calcium and the monomeric form heightened putatively excitotoxic, neuronal death, whereas, in the substantia nigra we saw inhibition, decreased intracellular calcium and monomeric α-synuclein was not associated with heightened cell death. These nucleus-specific differential effects suggest previously unappreciated, mechanistic underpinnings of SDs’ prodromal PD appearance in PD, and we hypothesize that in the prodromal phase of PD, the early form of α-synuclein compromises sleep-control neurons.