Protein in the Brain Could be New Drug Target for Schizophrenia

New study reveals that a protein present in the brain could be used to treat schizophrenia

Highlights:

Schizophrenia is a chronic brain disorder and its symptoms can include delusions, hallucinations, disorganized speech, trouble with thinking and lack of motivation
Increased amounts of the immunological protein C4 have been found in the brains of schizophrenia patients //
Targeting brain cells called astrocytes which secrete C4 may be key to treating schizophrenia

A recent study has identified a protein in the brain of patients with schizophrenia which can be targeted by drugs to treat the neurodegenerative disease. To identify effective drugs, researchers have developed an efficient method to make large numbers of C4-secreting human astrocytes from stem cells ().

The researchers followed-up with a screen of 464 drugs and identified a small group of about 20 that reduced C4 secretion from astrocytes. These drugs were effective in both healthy astrocytes and in astrocytes made from Schizophrenia patients' stem cells.

Astrocytes, which are brain cells, regulate the immune response and inflammatory environment in the brain by secreting immune proteins like C4. As a result, astrocytes are the principal target of C4-lowering therapy.

About Schizophrenia
Schizophrenia is a mental disorder characterized by symptoms of thought, behavior and social problems.

‘A protein identified in the brain could be a novel therapeutic target for schizophrenia.’

Linking C4 and Schizophrenia

There is a strong rationale for targeting the complement system as a therapeutic approach to improving brain function. Genetic variations in complement component 4 (C4) copy number have been linked to the increased risk of schizophrenia. In addition, schizophrenia patients exhibit elevated C4 expression in the cerebral cortex.

Although the exact mechanism underlying schizophrenia is unknown, C4 over-expression can lead to reduced thickness and synaptic density in the brain cortex of patients with schizophrenia.

Schizophrenia Diagnosis
No particular tests or methods are available to diagnose schizophrenia. Diagnosis of schizophrenia is done on the basis of the patient’s medical history.

Astrocytes in Brain and Schizophrenia

Astrocytes play a critical role in synapse formation, function, and elimination The contribution of astrocytes to neuropsychiatric and neurodegenerative diseases has been increasingly recognized. Astrocytes and microglia are considered the immune cells of the brain due to their ability to secrete chemokines and cytokines, complement proteins, and for their phagocytic function. In particular, astrocytes express and secrete complement components, such as C1r, C1s, C2, C3, and C4, which, therefore, may act cell non-autonomously.

Schizophrenia is a Cluster of Eight Diseases - Significant Breakthrough
Schizophrenia is not a single disease caused by one gene as previously thought, but a group of eight distinct genetic disorders, each with its own set of symptoms.

Importance of Complement System

The complement system is part of the first line of defense against harmful pathogens. While the primary site of complement synthesis is the liver, production of complement also happens in the central nervous system (CNS).

In addition to its role in CNS inflammation, the complement system shapes the developing brain by controlling synaptic refinement to ensure proper brain function. In the mature human brain, aberrant activation of the complement has been observed in the CNS of patients with neurodegeneration, autoimmune diseases, and aging.

Excessive complement activation gives rise to early synaptic loss, correlating with cognitive impairment in Alzheimer’s disease (AD) and Tauopathy. Blocking the complement system in vivo rescues aberrant synaptic pruning and attenuates neuroinflammation and neurodegeneration in mouse models of AD.

This study opens up new avenues for studying inflammatory responses and their regulation in human astrocytes and serves as a platform to identify therapeutic drugs in large-scale screening approaches.

Reference:

Small-molecule screen reveals pathways that regulate C4 secretion in stem cell-derived astrocytes - (https://pubmed.ncbi.nlm.nih.gov/36563689/)

Source-Medindia

Quiz on Schizophrenia
Schizophrenia is a mental disorder that affects young adults; nearly 7% of the adult population is affected by this condition. Check out how much you know about schizophrenia by taking this quiz.