Schizophrenia is a complex mental health disorder that can be very difficult to treat because there is still a lot we don’t know about the disease. It can present differently from one patient to another, and may lead to a variety of symptoms including delusions, hallucinations, disordered thoughts, or unusual behaviors. But researchers are revealing new details about it all the time, which may eventually lead to advances in diagnostics, treatments, or preventive options.
Reporting in Science Advances, researchers have now found that a change in how a certain gene is edited when active could be related to schizophrenia.
Active genes are transcribed into molecules called messenger RNA (mRNA), which is then processed and edited in various ways by the cell before being expressed as protein. Some genes can be edited, or spliced, in different ways in a process known as alternative splicing. Alternatively spliced mRNA transcripts of the same gene can lead to the production of very different proteins. An alternative splicing process related to a gene known as DOC2A has now been associated with schizophrenia.
Alternative splicing can happened due to very small changes in the sequence of a gene, or in so-called genetic variants. Some of these variants alter the genetic sequences but do not ultimately affect the amino acid sequence of the resulting protein.
There have been thousands of genetic variants that have been linked to schizophrenia. But scientists are still trying to decipher how many of these variants are connected to the disorder, and how they change biological functions and processes.
In this work, the investigators sought to understand more about the impact of genetic variants of DOC2A.
A variant or single nucleotide polypmorphism (SNP) known as rs3935873 was found to be most likely to trigger alternative splicing in DOC2A.
Further work indicated that variant leads to the production of a smaller protein, one called DOC2A△Val217–Pro218, but the full-length transcript of the gene is ultimately not affected. The expression of this variant in cells of the hippocampus caused behaviors that are related to schizophrenia in a mouse model such as anxiety, impaired movements, and anhedonia. Unaltered mice or mice that generated the full-length DOC2A transcript were not affected.
The work also showed that neurons with the schizophrenia-associated DOC2A variant exhibited enhanced excitatory synaptic transmission, and potentially, changes in synaptic transmission.
Sources: Science Advances
