Metabolic compromise, including mitochondrial dysfunction, may contribute to the development of symptoms in schizophrenia. However, approaches to explore the relationship between mitochondrial dysfunction, neural dysfunction, and schizophrenia risk are needed. The most common genetic risk factor for schizophrenia is the 22q11.2 deletion syndrome (22q11DS), associated with a 25% risk of developing this disorder. Interestingly, in 22q11DS six of the roughly 40 deleted genes encode for mitochondrial-localizing proteins. We have assembled a multidisciplinary team to combine the use of stem cell derived neurons from 22q11DS patients with or without schizophrenia, and controls, with genetic analyses of 22q11DS patients with and without schizophrenia. We will test the hypothesis that a ?second hit? within mitochondrial-related genes in the 22q11DS context increases metabolic dysfunction in neurons and is associated with an increased risk for schizophrenia in patients.
Aim 1. Investigation of mitochondrial function in 22q11DS derived forebrain neurons. Existing IPSC lines from 3 groups will be compared: 1) 22q11DS with schizophrenia, 2) 22qDS without schizophrenia or history of psychosis (and over the age of 25), and healthy controls. Forebrain-like neurons from these lines will be compared for evidence of mitochondrial dysfunction that is most pronounced in the 22q11DS+SZ group. Consistent with the fact that one of the 22q11-deleted genes is MRPL40, a subunit of the mitochondrial ribosome, our preliminary evidence suggests that IPSC-derived neurons from the 22q11DS+SZ group have reduced translation of COX1, a key mitochondrial DNA-encoded protein. They also have significantly reduced cytochrome C oxidase activity, and strong evidence of oxidative damage.
Aim 2. Are genetic ?second hits? to mitochondrial function associated with psychosis in 22q11DS? We will use whole genome sequence data from about 600 22q11DS patients, evenly split between those with and without chronic psychosis, from the International 22q11.2DS Brain and Behavior Consortium (22QIBBC). Bioinformatic processing will determine whether the risk of developing SZ in 22q11DS is potentially influenced by the mitochondrial haplogroup, or is associated with an increased presence of mutations in mtDNA, or is associated with an increased presence of mutations in nuclear-encoded genes that generate mitochondrial- functioning proteins. Future studies would employ mitochondrial cybrids (`swapping?) technology, genome editing, ?putback? experiments, and other approaches to test the functional relevance of findings from Aim 2 on mitochondrial function in 22q11DS-derived IPSCs, and could be extended to IPSCs from other high-risk SZ groups. These results could also be used to examine the prospective risk of 22q11DS children to develop chronic psychosis, using the large cohort of subjects currently being enrolled and studied by the 22QIBBC. Significance The results of this study could lead to improved prediction, treatment, and prevention of psychosis in 22q11DS, and could generalize to the treatment or prevention of psychosis beyond 22q11DS.

Public Health Relevance

Metabolic compromise, including mitochondrial dysfunction, may contribute to the development of symptoms in schizophrenia. The goal of this proposal is to test the hypothesis that, in 22q11 deletion syndrome, a ?second hit? within mitochondria-related genes increases metabolic dysfunction in neurons and is associated with an increased risk of schizophrenia in patients. Results of this study could lead to improved treatment, prediction, and prevention of psychosis in 22q11DS, and could generalize to other developmental neuropsychiatric sequelae of disruptions of mitochondrial function, and to the treatment or prevention of psychosis beyond 22q11DS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH110185-02
Application #
9355237
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Panchision, David M
Project Start
2016-09-20
Project End
2019-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104