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.