Altered steady state and activity-dependent de novo protein expression in fragile X syndrome

Heather Bowling; Aditi Bhattacharya; Guoan Zhang; Danyal Alam; Joseph Z. Lebowitz; Nathaniel Bohm-Levine; Derek Lin; Priyangvada Singha; Maggie Mamcarz; Rosemary Puckett; Lili Zhou; Sameer Aryal; Kevin Sharp; Kent Kirshenbaum; Elizabeth Berry-Kravis; Thomas A. Neubert; Eric Klann

doi:10.1038/s41467-019-09553-8

Altered steady state and activity-dependent de novo protein expression in fragile X syndrome

Heather Bowling, Aditi Bhattacharya, Guoan Zhang, Danyal Alam, Joseph Z. Lebowitz, Nathaniel Bohm-Levine, Derek Lin, Priyangvada Singha, Maggie Mamcarz, Rosemary Puckett, Lili Zhou, Sameer Aryal, Kevin Sharp, Kent Kirshenbaum, Elizabeth Berry-Kravis, Thomas A. Neubert, Eric Klann

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Abstract

Whether fragile X mental retardation protein (FMRP) target mRNAs and neuronal activity contributing to elevated basal neuronal protein synthesis in fragile X syndrome (FXS) is unclear. Our proteomic experiments reveal that the de novo translational profile in FXS model mice is altered at steady state and in response to metabotropic glutamate receptor (mGluR) stimulation, but the proteins expressed differ under these conditions. Several altered proteins, including Hexokinase 1 and Ras, also are expressed in the blood of FXS model mice and pharmacological treatments previously reported to ameliorate phenotypes modify their abundance in blood. In addition, plasma levels of Hexokinase 1 and Ras differ between FXS patients and healthy volunteers. Our data suggest that brain-based de novo proteomics in FXS model mice can be used to find altered expression of proteins in blood that could serve as disease-state biomarkers in individuals with FXS.

Original language	English (US)
Article number	1710
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-09553-8
State	Published - Dec 1 2019

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Bowling, H., Bhattacharya, A., Zhang, G., Alam, D., Lebowitz, J. Z., Bohm-Levine, N., Lin, D., Singha, P., Mamcarz, M., Puckett, R., Zhou, L., Aryal, S., Sharp, K., Kirshenbaum, K., Berry-Kravis, E., Neubert, T. A., & Klann, E. (2019). Altered steady state and activity-dependent de novo protein expression in fragile X syndrome. Nature communications, 10(1), [1710]. https://doi.org/10.1038/s41467-019-09553-8

Bowling, H, Bhattacharya, A, Zhang, G, Alam, D, Lebowitz, JZ, Bohm-Levine, N, Lin, D, Singha, P, Mamcarz, M, Puckett, R, Zhou, L, Aryal, S, Sharp, K, Kirshenbaum, K, Berry-Kravis, E, Neubert, TA & Klann, E 2019, 'Altered steady state and activity-dependent de novo protein expression in fragile X syndrome', Nature communications, vol. 10, no. 1, 1710. https://doi.org/10.1038/s41467-019-09553-8

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title = "Altered steady state and activity-dependent de novo protein expression in fragile X syndrome",

abstract = "Whether fragile X mental retardation protein (FMRP) target mRNAs and neuronal activity contributing to elevated basal neuronal protein synthesis in fragile X syndrome (FXS) is unclear. Our proteomic experiments reveal that the de novo translational profile in FXS model mice is altered at steady state and in response to metabotropic glutamate receptor (mGluR) stimulation, but the proteins expressed differ under these conditions. Several altered proteins, including Hexokinase 1 and Ras, also are expressed in the blood of FXS model mice and pharmacological treatments previously reported to ameliorate phenotypes modify their abundance in blood. In addition, plasma levels of Hexokinase 1 and Ras differ between FXS patients and healthy volunteers. Our data suggest that brain-based de novo proteomics in FXS model mice can be used to find altered expression of proteins in blood that could serve as disease-state biomarkers in individuals with FXS.",

author = "Heather Bowling and Aditi Bhattacharya and Guoan Zhang and Danyal Alam and Lebowitz, {Joseph Z.} and Nathaniel Bohm-Levine and Derek Lin and Priyangvada Singha and Maggie Mamcarz and Rosemary Puckett and Lili Zhou and Sameer Aryal and Kevin Sharp and Kent Kirshenbaum and Elizabeth Berry-Kravis and Neubert, {Thomas A.} and Eric Klann",

note = "Funding Information: We would like to acknowledge our lab members and collaborators for their input and discussion on the manuscript. We thank Dr. Nancy Gough of BioSerendipity for her help with the manuscript. This work was supported by FRAXA Research Foundation, NIH grants NS034007 and HD082013 to E.K., RR027990 and NS050276 to T.A.N. K.-K. acknowledges the support of the NSF (CHE-1507946). A.B. was supported by Charles H Revson Senior Biomedical Fellowship at NYU, and then by grants by the Department of Biotechnology, Government of India, and FRAXA Research Foundation at inStem. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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AU - Bhattacharya, Aditi

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AU - Lebowitz, Joseph Z.

AU - Bohm-Levine, Nathaniel

AU - Lin, Derek

AU - Singha, Priyangvada

AU - Mamcarz, Maggie

AU - Puckett, Rosemary

AU - Zhou, Lili

AU - Aryal, Sameer

AU - Sharp, Kevin

AU - Kirshenbaum, Kent

AU - Berry-Kravis, Elizabeth

AU - Neubert, Thomas A.

AU - Klann, Eric

N1 - Funding Information: We would like to acknowledge our lab members and collaborators for their input and discussion on the manuscript. We thank Dr. Nancy Gough of BioSerendipity for her help with the manuscript. This work was supported by FRAXA Research Foundation, NIH grants NS034007 and HD082013 to E.K., RR027990 and NS050276 to T.A.N. K.-K. acknowledges the support of the NSF (CHE-1507946). A.B. was supported by Charles H Revson Senior Biomedical Fellowship at NYU, and then by grants by the Department of Biotechnology, Government of India, and FRAXA Research Foundation at inStem. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

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N2 - Whether fragile X mental retardation protein (FMRP) target mRNAs and neuronal activity contributing to elevated basal neuronal protein synthesis in fragile X syndrome (FXS) is unclear. Our proteomic experiments reveal that the de novo translational profile in FXS model mice is altered at steady state and in response to metabotropic glutamate receptor (mGluR) stimulation, but the proteins expressed differ under these conditions. Several altered proteins, including Hexokinase 1 and Ras, also are expressed in the blood of FXS model mice and pharmacological treatments previously reported to ameliorate phenotypes modify their abundance in blood. In addition, plasma levels of Hexokinase 1 and Ras differ between FXS patients and healthy volunteers. Our data suggest that brain-based de novo proteomics in FXS model mice can be used to find altered expression of proteins in blood that could serve as disease-state biomarkers in individuals with FXS.

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Altered steady state and activity-dependent de novo protein expression in fragile X syndrome

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