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Searching for Schizophrenia Genes Using Cutting-Edge Technologies



For over 10 years, psychiatry researcher Pan Li, director of the Pathogenic Neurobiology Laboratory within the Division of Neurobiology, has focused her efforts on uncovering the molecular processes leading to neurodegenerative disorders such as Huntington’s disease and spinocerebellar ataxia. Now, with a new grant from the National Institutes of Mental Health, Li is turning her talents toward neuron cell development in schizophrenia.

Li’s lab already had established a precise, efficient genome editing protocol using CRISPR/Cas9 that allows investigators to edit genes of interest in cell lines of human induced pluripotent stem cells (iPSCs) to cause disease-like behavior and then reverse it. With the grant, Li and colleagues will introduce rare gene variants known to be affiliated with schizophrenia into human iPSC lines, then encourage those edited iPSCs to become neurons (nervous system cells) and characterize their cellular and electrophysiological phenotypes (characteristics) to look for shared or divergent cell signaling pathways that may play a role in the development of schizophrenia.

Li’s team will focus on seven genes identified by the Schizophrenia Exome Sequencing Meta-analysis (SCHEMA) consortium — a large multi-site collaboration dedicated to generating and analyzing sequencing data of schizophrenia patients — that contain ultra-rare coding variants that confer a substantial risk for developing the disorder. They are CUL1 and HERC1, which are involved in processes that maintain the function of proteins; SETD1A and SP4, which play a role in regulating the conversion of DNA to RNA; and GRIN2A, GRIA3 and CACNA1G, which are involved in transmission of messages from neuron to neuron. The group will study in-depth two mutations per gene. Investigators will use their gene editing tools to reduce the expression of the seven rare variant genes in neurons and use sequencing and other tools to assess the effects of these mutations.

“We are trying to aid schizophrenia diagnosis and also future treatment,” says Li, a faculty member with Johns Hopkins’ Precision Medicine Center of Excellence for Schizoaffective Disorders. “Schizophrenia is a heterogeneous disease. It’s clearly genetic, but there seems to be tons of mutations that can contribute. Also, the diagnosis right now is purely based on phenotype, so it is not yet completely accurate. Evaluating the rare variants identified by the SCHEMA consortium will help us evaluate how important they are to schizophrenia so in the future, if a patient has one of these variants, we could more clearly diagnose the condition.”

Since being awarded the grant, Li has recruited some postdoctoral fellows and students to work on the project and has created multiple edited human iPSC lines, each containing a different rare variant.

“Hopefully from our research, we can narrow down to a certain group of cells that are important to the development of schizophrenia, or a certain signaling pathway that seems to be implicated in schizophrenia, and find potential targets for new therapies,” says Li. “I am very blessed to receive this award from NIH.”


Hope for Huntington’s disease

CRISPR technology provides hope to treat Huntington’s disease, according to recent work by psychiatry researcher Wenzhen Duan, director of the Translational Neurobiology Laboratory; postdoctoral fellow Qian Wu; and colleagues. 

Duan’s team used CRISPR/Cas13d to target and cut toxic mRNA associated with Huntington’s disease in a mouse model of this devastating disease. The therapeutic approach depleted mutant Huntington RNA, improved motor coordination, attenuated degeneration of the striatum region of the brain and reduced toxic protein accumulation. These improvements lasted for at least eight months after a single injection without adverse side effects.   

The study was published in Nature Neuroscience.

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