FRANKFURT. Recent
studies have found a high genetic similarity of the psychiatric diseases
schizophrenia and bipolar disorder, whose disease-specific changes in brain
cells show an overlap of more than 70 percent. These changes affect gene
expression, i.e., transcription of genes for the purpose of translation into
functional proteins. A collaborative study carried out by the Institute of Pharmacology
and Clinical Pharmacy at 51猎奇 (Professor Jochen Klein) and the
Institute of Neurosciences at the Hebrew University of Jerusalem (Professor
Hermona Soreq) now shows sex-specific biases in these changes, as well as in cellular
control mechanisms based on endogenous short ribonucleic acid (RNA) chains.
The scientists identified an important
role of microRNAs, a special group of these small RNA molecules, known for
their extensive control of gene expression in all human cells. Targeting of a
gene by one of these microRNAs can lead to a significant restriction of its
expression. 鈥淭he main problem is the enormous variety of possible combinations,"
says Sebastian Lobentanzer, lead author of the article published in the journal
Cell Reports. 鈥淭he human expresses about 2,500 of these microRNAs, and a single
one can influence hundreds, maybe even thousands of genes."
For this reason, the researchers
investigated gene expression in patient brains as well as human cultured nerve
cells with a combination of RNA sequencing and bioinformatics. They found a
difference in the expression of immune-related genes between men and women,
especially with regard to cytokines, the messenger substances of immune cells. Upon
exposition of the cultured male and female neuronal cells to some of these
cytokines, the researchers found a transformation of nerve cells into to cholinergic
neurons, defined by their use of the neurotransmitter 鈥渁cetylcholine".
By sequencing the microRNAs at several time
points during this process, the scientists were able to paint a detailed
picture of the microRNA interface between the immune and neuronal systems. They
identified the involvement of 17 partially sex-dependent families of microRNAs
and generated an extensive network of 12,495 regulated genes. Using a multi-stage
selection process, the most influential of these microRNA families were
identified and confirmed in dedicated experiments. This led to the
identification of the two sex-specifically expressed families mir-10 and
mir-199 as interface between cytokines and cholinergic functions.
Psychiatric diseases are an important
field for new therapeutic approaches because of their high genetic complexity
and their inaccessibility to conventional forms of therapy. On the one hand, the
current study demonstrates molecular parallels to the long-observed but
previously unexplained clinical differences between disease-affected men and
women. On the other hand, mechanisms on the basis of small RNA molecules could
open up new avenues by influencing a large number of disease-relevant genes 鈥� a
promising approach in the search for alternatives to traditional antipsychotic drugs.
鈥淪tudies such as ours, which enable a comprehensive representation of microRNA interactions,
are the first step on the path to developing new therapeutic substances," says
Lobentanzer.
Publication:
Lobentanzer S, Hanin G, Klein J & Soreq H (2019). Integrative
Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine
Interface in Schizophrenia and Bipolar Disorder. CellReports. ElsevierCompany.
1鈥�19. doi: 10.1016/j.celrep.2019.09.017.
An image may
be downloaded here:
Caption:
The illustration shows a network of 212
microRNAs and their 12,495 targeted genes, deconstructed into four fields
according to their sex-specific changes. (Copyright:
Sebastian Lobentanzer)
Further information: Sebastian Lobentanzer, research scientist; Professor Jochen Klein;
Institute for Pharmacology and Clinical Pharmacy, Riedberg Campus; lobentanzer@em.uni-frankfurt.de, klein@em.uni-frankfurt.de. .
