The Prokineticin System Is Downregulated in Idiopathic Rapid Eye Movement Sleep Behavior Disorder: Evidence from Olfactory Neurons

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ABSTRACT 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 and 28 healthy controls (HCs), 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 samples. Results In the iRBD group, PROK2 protein expression was reduced in both ONs (IF: F(1,26)=15.289, p<0.001; WB: F(1,12)=9.073, p=0.011) and serum compared with HCs (WB: F(1,12)=4.557, p=0.050). iRBD subjects showed lower mRNA expression of prokineticin receptors compared with HCs (RT-PCR for PKR1: F(1,26)=16.131, p<0.001; RT-PCR for PKR2: F(1,39)=4.946, p=0.032). 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=0.092). Conclusion 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 a 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. Statement of significance This study reveals a downregulation of the prokineticin system in individuals with Idiopathic Rapid Eye Movement Sleep Behavior Disorder (iRBD), a prodromal stage of Parkinson’s disease (PD). Prokineticin-2 (PROK2) is a peptide expressed in the adult brain mediating neuroprotective functions. In contrast to the upregulation reported in established PD, the downregulation observed in iRBD suggests a failure to activate endogenous neuroprotective mechanisms at the prodromal stage of disease, providing new insight into early processes that may predispose to neurodegeneration. Notably, the prokineticin pathway was investigated in olfactory neurons obtained through a simple, non-invasive nasal brushing, demonstrating that these cells represent an innovative and accessible source of biomarkers for central nervous system disorders.

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