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 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 REM sleep behavior disorder (iRBD). Methods: ONs, obtained by nasal brush from 28 iRBD 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 iRBD group, PROK2 protein expression was reduced in both ONs (IF: F(1,26) = 15.289, p<.001; WB: F(1,12) = 9.073, p=.011) and serum compared with HCs (WB: F(1,12) = 4.557, p=.050). iRBD subjects showed lower mRNA expression of prokineticin receptors compared with HCs (RT-PCR for PKR1: F(1,26) = 16.131, p<.001; RT-PCR for PKR2: F(1,39) = 4.946, p=.032). Oligo α-syn accumulation in ONs was higher in iRBD than HCs, yet the difference only tended to statistical significance (IF: F(1,18) = 3.169, p=.092). Conclusions: In contrast with findings in PD, we found a downregulation of prokineticin system in iRBD. The causes of prokineticin system downregulation in this prodromal stage may be multiple. The absence of clear oligo α-syn accumulation, known trigger of PROK2, may play a role. On the other hand, a lack of activation of this system might act as predisposing factor for the development of iRBD and, subsequently, full-blown neurodegeneration.