Abnormal levels of mitochondrial Ca ²⁺ channel proteins in plasma neuron‐derived extracellular vesicles of early schizophrenia

Abstract

Structural alterations or quantitative abnormalities of some mitochondrial ion channels and exchangers are associated with altered neuronal functions and increased susceptibility to mental illness. Here we have assessed levels of functionally prominent mitochondrial calcium ion channel proteins in plasma neuron‐derived extracellular vesicles (NDEVs) of living patients with first episodes of psychosis (FP) and matched controls (Cs). NDEVs were enriched with an established method of precipitation and immunoabsorption by anti‐human CD171 neural adhesion protein (L1CAM) antibody and extracted proteins quantified with ELISAs. CD81 exosome marker‐normalized NDEV levels of leucine zipper EF‐hand containing transmembrane 1 protein (LETM1), transient receptor potential cation channel subfamily M, member 4 (TRPM4), and solute carrier family 8 member B1 (SLC24A6) or mitochondrial Na+/Ca2+ exchanger (NCLX) were significantly lower for FP patients (n = 10) than Cs (n = 10), whereas NDEV levels of voltage‐dependent L‐type calcium channel subunit α‐1C (CACNA‐1C) were significantly higher for FP patients than Cs. Abnormal structures or mitochondrial levels of LETM1, NCLX, and CACNA‐1C have been linked through analyses of individual proteins, genome‐wide association studies, and whole exome protein‐coding sequence studies to neurodevelopmental disorders, mental retardation, schizophrenia, and major depressive diseases. A greater understanding of the altered calcium homeostasis in schizophrenia, that is attributable to underlying mitochondrial calcium channel abnormalities, will lead to improved diagnosis and treatment.

Neuron-derived extracellular vesicles in blood reveal effects of exercise in Alzheimer’s disease

“…Plasma humanin decreases with age in humans and mice [ 43 ], and upon replenishment, cognition in aged mice is improved [ 44 ]. Humanin mRNA in plasma EVs has been found decreased in AD compared to control individuals [ 45 ], whereas protein levels of humanin in NDEVs have been found decreased in multiple neuropsychiatric disorders [ 46 , 47 ]. Interestingly, physical activity increases humanin in plasma [ 48 ].…”

The role of Extracellular Genomic Materials (EGMs) in psychiatric disorders

“…There was no difference between the groups in the amount and size of exosomes [ 118 ]. Again by the same group, a significant decrease in mitochondrial functional protein levels such as ATP synthase, mitofusin 2, and cyclophilin in astrocyte and neuron-derived exosomes in patients with first-episode psychosis in astrocyte-derived extracellular vesicles and NDEVs [ 119 ] and altered levels of mitochondrial calcium ion channel proteins such as an increased level of CACNA- 1C and decreased levels of LETM1, NCLX, SLC24A6, and TRPM4 in plasma NDEVs of patients with first-episode psychosis [ 120 ] have been reported. In another study, it was shown that Aβ42 levels in astrocyte-derived exosomes (ACE) were higher in patients with schizophrenia compared to controls, and high exosome ACE-P-T181-tau levels in the whole sample were associated with impaired executive functions [ 121 ].…”

Urinary Astrocyte-derived Extracellular Vesicles: A Non-invasive Tool for Capturing HumanIn VivoMolecular “Movies” of Brain

“…Theoretically, uTEVs may also contain EVs derived from other CNS cells, such as neurons and various types of glial cells, including microglia and oligodendrocytes, which could be isolated using similar methods. For other types of BDEVs, such as NDEVs, L1 cell adhesion molecule (L1CAM) is commonly used as a marker [55][56][57] . However, L1CAM expression is also detected in the kidney 58 , potentially compromising the purity of urinary L1CAM + EVs that are truly derived from CNS.…”