Olfactory Neuron Prokineticin‐2 as a Potential Target in Parkinson's Disease

Abstract

Objective The objective of this study was to outline the dynamics of prokineticin‐2 pathway in relation to clinical‐pathological features of Parkinson's disease by examining olfactory neurons of patients. Methods Thirty‐eight patients (26 de novo, newly diagnosed) and 31 sex/age‐matched healthy controls underwent noninvasive mucosa brushing for olfactory neurons collection, and standard clinical assessment. Gene expression levels of prokineticin‐2, prokineticin‐2 receptors type 1 and 2, and prokineticin‐2‐long peptide were measured in olfactory neurons by real‐time polymerase chain reaction (PCR); moreover, the prokineticin‐2 protein and α‐synuclein species (total and oligomeric) were quantified by immunofluorescence staining. Results Prokineticin‐2 expression was significantly increased in Parkinson's disease. De novo patients had higher prokineticin‐2 levels, directly correlated with Movement Disorder Society‐Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS‐UPDRS) part III motor score. In addition, oligomeric α‐synuclein was higher in Parkinson's disease and directly correlated with prokineticin‐2 protein levels. Total α‐synuclein did not differ between patients and controls. Interpretation Prokineticin‐2 is a chemokine showing neuroprotective effects in experimental models of Parkinson's disease, but translational proof of its role in patients is still lacking. Here, we used olfactory neurons as the ideal tissue to analyze molecular stages of neurodegeneration in vivo, providing unprecedented evidence that the prokineticin‐2 pathway is activated in patients with Parkinson's disease. Specifically, prokineticin‐2 expression in olfactory neurons was higher at early disease stages, proportional to motor severity, and associated with oligomeric α‐synuclein accumulation. These data, consistently with preclinical findings, support prokineticin‐2 as a candidate target in Parkinson's disease, and validate reliability of olfactory neurons to reflect pathological changes of the disease. ANN NEUROL 2023;93:196–204

Sex hormones differentially contribute to Parkinson disease in males: A multimodal biomarker study

“…We found that estradiol levels were higher in patients at the beginning of the disease and in those with milder motor impairment or lesser impact of motor fluctuations, consistent with the well-known protective effect of estradiol, as seen in female patients [20] and animal models [23]. The reasons underlying the decline of estradiol levels along the disease course cannot be established here, but it may shape other protective or compensatory mechanisms, weakening along the PD clinical-pathological progression [24].…”

Substance P and Prokineticin-2 are overexpressed in olfactory neurons and play differential roles in persons with persistent post-COVID-19 olfactory dysfunction

“…In particular, because efficient ONs mitochondria are critical for proper olfactory signalling ( Fluegge et al, 2012 ), we could hypothesize that PK2, by the stimulation of mitochondrial activity, may improve olfaction, counteracting detrimental effects of chronic inflammation and SP, which instead aggravate oxidative stress and mitochondrial impairment ( Wang et al, 2014 ). Indeed, the potential of PK2 as a neuroprotective mediator has been recently presented in Parkinson’s disease, where patients at the early stages of the disease exhibit increased levels within the ONs ( Schirinzi et al, 2022 ).…”

“…All participants underwent non-invasive olfactory mucosa brushing for ONs collection by expert otolaryngologists as described in ( Brozzetti et al, 2020 , Schirinzi et al, 2022 , Stefani et al, 2021 ). After inspection of the nose under nasal endoscopic view, ONs were collected through a specifically designed flocked nasal brush (FLOQBrushTM, Copan Italia Spa, Brescia, Italy).…”

“…Immunofluorescence staining was, instead, performed to investigate the ONs expression pattern and cellular localization of SP and PK2. Assays were run in blind as previously described ( Schirinzi et al, 2022 ).…”

“…By the non-invasive brushing of the olfactory mucosa, olfactory neurons (ONs) can be easily collected and analysed to examine molecular events related to pathological conditions ( Brozzetti et al, 2020 , Orrú et al, 2014 , Schirinzi et al, 2022 ). In this study, we went to characterize the activation profile of SP and PK2 pathways in ONs of patients with persistent post-COVID-19 OD, aimed at dissecting the underlying mechanisms of such a disabling phenomenon.…”