Schizophrenia is a severe, debilitating, neurodevelopmental disorder that affects 1% of the world's population. Recent findings from our laboratory have identified reduced levels of fragile X mental retardation protein (FMRP) and several downstream FMRP targets in superior frontal cortex of individuals with schizophrenia. We hypothesized that altered subcellular expression of FMRP and its signaling partners may explain these changes. In the current study we employed subcellular fractionation and western blotting to determine levels of FMRP, phosphorylated-FMRP as well as selected signaling partners [protein phosphatase 2A catalytic subunit (PP2AC), p70 S6 kinase (p70 S6K), and amyloid-ß A4 precursor protein (APP)] in the total homogenate, nuclear, and rough endoplasmic reticulum fractions in superior frontal cortex of individuals with schizophrenia versus controls (N = 12/group). In total homogenate of individuals with schizophrenia, we identified significantly lower levels of FMRP, phosphorylated-FMRP, and PP2AC. In the nuclear fraction of individuals with schizophrenia we found significantly higher levels of PP2AC, p70 S6K, APP 120 kDa, and APP 88 kDa proteins. Finally, in rough endoplasmic reticulum of individuals with schizophrenia, we identified significantly lower protein levels of p70 S6K and APP 120 kDa. These results provide evidence for a potential mechanism to explain altered FMRP expression in schizophrenia.
Bibliographical noteFunding Information:
This work is supported by the Winston and Maxine Wallin Neuroscience Discovery Fund. S.H. Fatemi is also supported by the Bernstein Endowed Chair in Adult Psychiatry. Tissue samples from the Harvard Brain Tissue Resource Center, which is supported in part by PHS grant number R24 MH068855 is gratefully acknowledged. Technical advice on subcellular fractionation technique from Dr. J.H. Meador-Woodruff, Dr. T.M. Mueller, and Mr. M.S. Simmons is gratefully acknowledged.
- endoplasmic reticulum