The Prokineticin system is downregulated in idiopathic rapid eye movement sleep behavior disorder: evidence from olfactory neurons

Study Objectives: PROK2 is a peptide expressed in the adult brain mediating neuroprotective functions. Previous studies reported an upregulation of prokineticin system in Parkinson’s disease (PD), but evidence in prodromal α-synucleinopathies was lacking. We investigated the expression of prokineticin-2 (PROK2) and its receptors (PKR1 and PKR2), along with oligomeric α-synuclein (oligo α-syn) as a marker of α-synuclein pathology, in olfactory neurons (ONs) from individuals with idiopathic rapid eye movement sleep behavior disorder (iRBD). Methods: Olfactory neurons, obtained by nasal brush from 28 idiopathic rapid eye movement sleep behavior disorder subjects (age: 71.2 ± 7.4 years; males: 89.3%; duration: 4.9 ± 2.5 years) and 28 healthy controls (HCs) (age:67.2 ± 11.5 years; males:64.2%), were analyzed using real-time polymerase-chain-reaction (RT-PCR), immunofluorescence (IF), and western blot (WB). In a subgroup of subjects, results were validated in serum. Results: In the idiopathic rapid eye movement sleep behavior disorder group, prokineticin-2 protein expression was reduced in both ONs (immunofluorescence: F(1,26) = 15.289, p < .001; western blot: F(1,12) = 9.073, p = .011) and serum compared with HCs (western blot: F(1,12) = 4.557, p = .050). Idiopathic rapid eye movement sleep behavior disorder subjects showed lower mRNA expression of prokineticin receptors compared with healthy controls (real-time polymerase-chain-reaction for prokineticin receptor-1: F(1,26) = 16.131, p < .001; real-time polymerase-chain-reaction for prokineticin receptor-2: F(1,39) = 4.946, p = .032). Oligo α-syn accumulation in olfactory neurons was higher in idiopathic rapid eye movement sleep behavior disorder than healthy controls, yet the difference only tended to statistical significance (immunofluorescence: F(1,18) = 3.169, p = .092). Conclusions: In contrast with findings in Parkinson’s disease, we found a downregulation of prokineticin system in idiopathic rapid eye movement sleep behavior disorder. The causes of prokineticin system downregulation in this prodromal stage may be multiple. The absence of clear oligo α-syn accumulation, known trigger of prokineticin-2, may play a role. On the other hand, a lack of activation of this system might act as predisposing factor for the development of idiopathic rapid eye movement sleep behavior disorder and, subsequently, full-blown neurodegeneration.