Can the Imbalance between Neurotrophic and Apoptotic Proteins Be the “Beware the Ides of March” for Unaffected Relatives of Schizophrenia Patients?

Abstract

Schizophrenia (SZ) is a mental disorder with a strong genetic basis as well as epigenetic aspects. Siblings of patients with SZ can share certain endophenotypes with the patients, suggesting that the siblings may be important for distinguishing between trait and state markers. In the current study, we aimed to characterize the balance between pro-BDNF/mature BDNF and its receptors p75NTR/TrkB, which is tpa-BDNF pathways proteins and thought to play a role in synaptic pruning as a possible endophenotype of schizophrenia. Forty drug-naïve patients with rst-episode psychosis (FEP) matched for age, gender and level of education, 40 unaffected siblings (UAS) of patients with FEP and 67 healthy controls (HC) were included in the study. Blood samples were collected from all participants to determine BDNF, pro-BDNF, TrkB and p75NTR, PAI1, tPA, ACTH and cortisol levels. We showed that levels of proteins of the tPA-BDNF pathway, pro-BDNF/m-BDNF and p75NTR/TrkB ratios could successfully differentiateFEP and their siblings from the HCs by using ROC analysis. Plasma levels of m-BDNF were found to be the lowest in the healthy siblings and highest in the healthy control group with statistically signi cant differences between all 3 groups. The plasma levels of pro-BDNF in the healthy control group were similar to the FEP patients, the same in the healthy siblings of the FEP patients. Our data Support the hypothesis that imbalance between neurotrophic and apoptotic proteins might occur in SZ, and this imbalance could be an endophenotype of the disease.

The potential role of the p75 receptor in schizophrenia: neuroimmunomodulation and making life or death decisions

“…Increased plasma levels of p75 receptor protein are reported in first-episode psychosis patients compared to clinical high-risk individuals and controls ( He et al, 2019 ), with higher ratios of p75/TrkB protein found in serum of first-episode psychosis patients compared to unaffected siblings and controls ( Yesilkaya et al, 2022 ), reflecting a trophic imbalance preceding diagnosis and treatment that may favour apoptotic functions of the receptor. Whilst plasma p75 protein levels were found to positively correlate with positive and negative symptom scores in schizophrenia ( Zakowicz et al, 2023 ), other studies report no changes in p75 protein in the plasma of schizophrenia patients compared to controls ( Haack et al, 1999 ; Yesilkaya et al, 2022 ), with some reporting lower serum levels of p75 receptor protein ( Zakharyan et al, 2014 ; Chen et al, 2017 ; Turhan et al, 2016 ). A potential contributor to the heterogeneous results of studies assessing peripheral p75 receptor expression in schizophrenia is the prevalence of single nucleotide polymorphisms (SNPs) of the p75 receptor evident in patients.…”