Prodynorphin and Proenkephalin in Cerebrospinal Fluid of Sporadic Creutzfeldt-Jakob Disease.

Samir Abu-Rumeileh,Andrea Mastrangelo,Peggy Barschke,Mhd Rami Al Shweiki,Piero Parchi,Angela Mammana,Markus Otto,Petra Steinacker,Anna Ladogana,Simone Baiardi,Patrick Oeckl,Sabina Capellari

doi:10.3390/ijms23042051

Abstract

Proenkephalin (PENK) and prodynorphin (PDYN) are endogenous opioid peptides mainly produced in the striatum and, to a lesser extent, in the cerebral cortex. Dysregulated metabolism and altered cerebrospinal fluid (CSF) levels of PENK and PDYN have been described in several neurodegenerative diseases. However, no study to date investigated these peptides in the CSF of sporadic Creutzfeldt–Jakob disease (sCJD). Using liquid chromatography-multiple reaction monitoring mass spectrometry, we evaluated the CSF PDYN- and PENK-derived peptide levels in 25 controls and 63 patients with sCJD belonging to the most prevalent molecular subtypes (MM(V)1, VV2 and MV2K). One of the PENK-derived peptides was significantly decreased in each sCJD subtype compared to the controls without a difference among subtypes. Conversely, PDYN-derived peptides were selectively decreased in the CSF of sCJD MV2K, a subtype with a more widespread overall pathology compared to the sCJD MM(V)1 and the VV2 subtypes, which we confirmed by semiquantitative analysis of cortical and striatal neuronal loss and astrocytosis. In sCJD CSF PENK and PDYN were associated with CSF biomarkers of neurodegeneration but not with clinical variables and showed a poor diagnostic performance. CSF PDYN and PENK-derived peptides had no significant diagnostic and prognostic values in sCJD; however, the distinct marker levels between molecular subtypes might help to better understand the basis of phenotypic heterogeneity determined by divergent neuronal targeting.

Highlights

Sporadic Creutzfeldt–Jakob disease is the most common human prion disease and includes six distinct clinicopathological subtypes that are mainly determined by the genotype at the methionine (M)/valine (V) polymorphic codon 129 of the PRNP gene and type (1 or 2) of the disease-associated prion protein (PrPSc ) accumulating in the brain.They have been named as MM(V)1, MM2 with predominant cortical pathology (MM2C), MM2 with predominant thalamic degeneration (MM2T), MV2 with kuru-type amyloid plaques (MV2K), VV1 and VV2 [1,2].Several biofluid markers of neuronal damage, neuroinflammation and synaptic dysfunction have been evaluated in sCJD, aiming to improve diagnosis, prognostic evaluation, stratification and management of patients [3–6]
Endogenous opioids are a group of peptides that act on opioids receptors and that derive from proteolytic cleavage of three main precursors: proenkephalin (PENK), prodynorphin (PDYN) and pro-opiomelanocortin [7]
Using our previously developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) method in multiple reaction monitoring (MRM) mode for the measurement of cerebrospinal fluid (CSF) PDYN-derived peptides [9] and a new assay for PENK-derived peptides, we investigated the profiles of these markers in sCJD, including its molecular subtypes, and studied the possible associations between the neuropeptide levels and those of other biomarkers and clinical variables, such as disease stage and survival

Summary

Introduction

Sporadic Creutzfeldt–Jakob disease (sCJD) is the most common human prion disease and includes six distinct clinicopathological subtypes that are mainly determined by the genotype at the methionine (M)/valine (V) polymorphic codon 129 of the PRNP gene and type (1 or 2) of the disease-associated prion protein (PrPSc ) accumulating in the brain.They have been named as MM(V), MM2 with predominant cortical pathology (MM2C), MM2 with predominant thalamic degeneration (MM2T), MV2 with kuru-type amyloid plaques (MV2K), VV1 and VV2 [1,2].Several biofluid markers of neuronal damage, neuroinflammation and synaptic dysfunction have been evaluated in sCJD, aiming to improve diagnosis, prognostic evaluation, stratification and management of patients [3–6]. Sporadic Creutzfeldt–Jakob disease (sCJD) is the most common human prion disease and includes six distinct clinicopathological subtypes that are mainly determined by the genotype at the methionine (M)/valine (V) polymorphic codon 129 of the PRNP gene and type (1 or 2) of the disease-associated prion protein (PrPSc ) accumulating in the brain. They have been named as MM(V), MM2 with predominant cortical pathology (MM2C), MM2 with predominant thalamic degeneration (MM2T), MV2 with kuru-type amyloid plaques (MV2K), VV1 and VV2 [1,2]. Altered levels of CSF PDYN and/or PENK-derived peptides have been reported in Alzheimer’s disease (AD), frontotemporal dementia (FTD), dementia with

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