Blood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria

Abstract Phenylketonuria (PKU) is a genetic deficiency of phenylalanine hydroxylase (PAH) in liver resulting in blood phenylalanine (Phe) elevation and neurotoxicity. A pegylated phenylalanine ammonia lyase (PEG-PAL) metabolizing Phe into cinnamic acid was recently approved as treatment for PKU pati...

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Autores principales:	Rachna Manek, Yao V. Zhang, Patricia Berthelette, Mahmud Hossain, Cathleen S. Cornell, Joseph Gans, Gulbenk Anarat-Cappillino, Sarah Geller, Robert Jackson, Dan Yu, Kuldeep Singh, Sue Ryan, Dinesh S. Bangari, Ethan Y. Xu, Sirkka R. M. Kyostio-Moore
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f3a454c49a4a458db2c91e87d25ee520
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spelling	oai:doaj.org-article:f3a454c49a4a458db2c91e87d25ee5202021-11-28T12:17:45ZBlood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria10.1038/s41598-021-02267-22045-2322https://doaj.org/article/f3a454c49a4a458db2c91e87d25ee5202021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02267-2https://doaj.org/toc/2045-2322Abstract Phenylketonuria (PKU) is a genetic deficiency of phenylalanine hydroxylase (PAH) in liver resulting in blood phenylalanine (Phe) elevation and neurotoxicity. A pegylated phenylalanine ammonia lyase (PEG-PAL) metabolizing Phe into cinnamic acid was recently approved as treatment for PKU patients. A potentially one-time rAAV-based delivery of PAH gene into liver to convert Phe into tyrosine (Tyr), a normal way of Phe metabolism, has now also entered the clinic. To understand differences between these two Phe lowering strategies, we evaluated PAH and PAL expression in livers of PAHenu2 mice on brain and liver functions. Both lowered brain Phe and increased neurotransmitter levels and corrected animal behavior. However, PAL delivery required dose optimization, did not elevate brain Tyr levels and resulted in an immune response. The effect of hyperphenylalanemia on liver functions in PKU mice was assessed by transcriptome and proteomic analyses. We observed an elevation in Cyp4a10/14 proteins involved in lipid metabolism and upregulation of genes involved in cholesterol biosynthesis. Majority of the gene expression changes were corrected by PAH and PAL delivery though the role of these changes in PKU pathology is currently unclear. Taken together, here we show that blood Phe lowering strategy using PAH or PAL corrects both brain pathology as well as previously unknown lipid metabolism associated pathway changes in liver.Rachna ManekYao V. ZhangPatricia BertheletteMahmud HossainCathleen S. CornellJoseph GansGulbenk Anarat-CappillinoSarah GellerRobert JacksonDan YuKuldeep SinghSue RyanDinesh S. BangariEthan Y. XuSirkka R. M. Kyostio-MooreNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rachna Manek Yao V. Zhang Patricia Berthelette Mahmud Hossain Cathleen S. Cornell Joseph Gans Gulbenk Anarat-Cappillino Sarah Geller Robert Jackson Dan Yu Kuldeep Singh Sue Ryan Dinesh S. Bangari Ethan Y. Xu Sirkka R. M. Kyostio-Moore Blood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria
description	Abstract Phenylketonuria (PKU) is a genetic deficiency of phenylalanine hydroxylase (PAH) in liver resulting in blood phenylalanine (Phe) elevation and neurotoxicity. A pegylated phenylalanine ammonia lyase (PEG-PAL) metabolizing Phe into cinnamic acid was recently approved as treatment for PKU patients. A potentially one-time rAAV-based delivery of PAH gene into liver to convert Phe into tyrosine (Tyr), a normal way of Phe metabolism, has now also entered the clinic. To understand differences between these two Phe lowering strategies, we evaluated PAH and PAL expression in livers of PAHenu2 mice on brain and liver functions. Both lowered brain Phe and increased neurotransmitter levels and corrected animal behavior. However, PAL delivery required dose optimization, did not elevate brain Tyr levels and resulted in an immune response. The effect of hyperphenylalanemia on liver functions in PKU mice was assessed by transcriptome and proteomic analyses. We observed an elevation in Cyp4a10/14 proteins involved in lipid metabolism and upregulation of genes involved in cholesterol biosynthesis. Majority of the gene expression changes were corrected by PAH and PAL delivery though the role of these changes in PKU pathology is currently unclear. Taken together, here we show that blood Phe lowering strategy using PAH or PAL corrects both brain pathology as well as previously unknown lipid metabolism associated pathway changes in liver.
format	article
author	Rachna Manek Yao V. Zhang Patricia Berthelette Mahmud Hossain Cathleen S. Cornell Joseph Gans Gulbenk Anarat-Cappillino Sarah Geller Robert Jackson Dan Yu Kuldeep Singh Sue Ryan Dinesh S. Bangari Ethan Y. Xu Sirkka R. M. Kyostio-Moore
author_facet	Rachna Manek Yao V. Zhang Patricia Berthelette Mahmud Hossain Cathleen S. Cornell Joseph Gans Gulbenk Anarat-Cappillino Sarah Geller Robert Jackson Dan Yu Kuldeep Singh Sue Ryan Dinesh S. Bangari Ethan Y. Xu Sirkka R. M. Kyostio-Moore
author_sort	Rachna Manek
title	Blood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria
title_short	Blood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria
title_full	Blood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria
title_fullStr	Blood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria
title_full_unstemmed	Blood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria
title_sort	blood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f3a454c49a4a458db2c91e87d25ee520
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Blood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria

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