Phenylketonuria: towards mechanism-based treatment

Martijn Jonathan de Groot

Phenylketonuria: towards mechanism-based treatment

Vertaalde titel van de bijdrage: Fenylketonurie: naar mechanisme-gebaseerde behandeling

Martijn Jonathan de Groot

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Dit proefschrift onderzoekt hoe fenylketonurie (PKU) leidt tot een verstoorde werking van de hersenen. PKU is een aangeboren ziekte van de fenylalaninestofwisseling, die onbehandeld leidt tot een ernstige ontwikkelingsachterstand. Bij een vroege diagnose en behandeling met een fenylalaninebeperkt dieet is de ontwikkeling vrijwel normaal. De hersenfuncties blijven echter verstoord en de strenge dieetbehandeling verlaagt de kwaliteit van leven. Bij onze studies in PKU patiënten zagen we dat hogere fenylalanineconcentraties in het bloed geassocieerd waren met minder 11C-tyrosine transport. Zowel minder 11C-tyrosine transport als een hogere fenylalanineconcentratie in het brein was sterk geassocieerd met minder eiwitaanmaak in de hersenen. Deze verbanden hebben we verder onderzocht in PKU muizen. Hoewel onbehandelde PKU muizen diverse biochemische veranderingen hadden in het bloed en in de hersenen, hadden ze geen leer- en geheugenproblemen in gedragstesten. Om deze situatie beter te begrijpen, hebben we het pCREB/CREB systeem onderzocht, dat biochemische veranderingen koppelt aan leren en geheugenvorming. Dit systeem was onder basale omstandigheden minder actief bij PKU muizen, maar deze verlaagde activiteit normaliseerde na gedragstesten. Dit suggereert dat het herstellen van de verlaagde pCREB/CREB activiteit leren en geheugenvorming bij PKU muizen intact houdt. In andere gedragstesten, waarbij boodschapperstoffen in de hersenen betrokken zijn, hadden PKU muizen diverse afwijkingen. Deze gedragsafwijkingen gingen gepaard met verlaagde concentraties van de boodschapperstoffen. Een monotherapeutische benadering om deze concentraties te herstellen was ineffectief. Mogelijk zijn er meerdere interventies tegelijk nodig. Bovenstaande bevindingen bieden aangrijppunten voor nieuwe PKU behandelingen, met als doel de ontwikkeling en kwaliteit van leven te verbeteren.

Vertaalde titel van de bijdrage	Fenylketonurie: naar mechanisme-gebaseerde behandeling
Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Toekennende instantie	Rijksuniversiteit Groningen
Begeleider(s)/adviseur	van Spronsen, Francjan, Supervisor van der Zee, Eddy, Supervisor Reijngoud, Dirk Jan, Co-supervisor
Datum van toekenning	27-mei-2015
Plaats van publicatie	[Groningen]
Uitgever	University of Groningen
Gedrukte ISBN's	978-90-367-7809-1
Elektronische ISBN's	978-90-367-7808-4
Status	Published - 2015

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Title and contentsFinal publisher's version, 674 KB
Chapter_2Final publisher's version, 966 KB
Chapter 4Final publisher's version, 1,2 MB
Chapter 6Final publisher's version, 749 KB
Chapter 8Final publisher's version, 1,15 MB
Samenvatting in het NederlandsFinal publisher's version, 706 KB
DankwoordFinal publisher's version, 635 KB
List of publicationsFinal publisher's version, 627 KB
Complete thesisFinal publisher's version, 3,55 MB
PropositionsFinal publisher's version, 560 KB
Curriculum vitaeFinal publisher's version, 652 KB
Chapter 5Final publisher's version, 894 KB
Chapter 7Final publisher's version, 918 KB
Chapter 1Final publisher's version, 730 KB
Chapter 3Final publisher's version, 1,58 MB

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title = "Phenylketonuria: towards mechanism-based treatment",

abstract = "This thesis investigates the mechanisms by which phenylketonuria (PKU) results in brain dysfunction. PKU is an inherited disease characterized by impaired phenylalanine (Phe) metabolism, leading to severe mental retardation. When diagnosed early in life and adequately treated by a Phe-restricted diet, mental development is within normal ranges. However, outcome remains suboptimal, and the strict treatment reduces quality of life. We found that in PKU patients, higher blood Phe concentrations were associated with less 11C-tyrosine transport, which in turn was strongly related with less cerebral protein synthesis (CPS). Moreover, higher brain Phe concentrations were strongly associated with less CPS. These associations were further studied in a PKU mouse model. Untreated PKU mice showed several characteristic biochemical changes in blood and brain. Unexpectedly, these mice did not show learning and memory deficits in behavioral tasks. To clarify these phenotypic differences, we studied the pCREB/CREB signaling system, which connects biochemical markers to learning and memory. While the pCREB/CREB system was less active in PKU mice under baseline conditions, its activity normalized after behavioral testing. These results suggest that PKU mice maintain learning and memory by upregulating the pCREB/CREB system. In behavioral tasks associated with monoaminergic neurotransmitter signaling, PKU mice displayed several deficits, which were paralleled by reduced brain concentrations of these neurotransmitters. A monotherapeutic approach to restore these abnormalities was ineffective, suggesting that multiple interventions may be required. Together, our findings suggest several targets for developing mechanism-based therapies in PKU. Such therapies will likely improve treatment outcome and quality of life.",

author = "{de Groot}, {Martijn Jonathan}",

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N2 - This thesis investigates the mechanisms by which phenylketonuria (PKU) results in brain dysfunction. PKU is an inherited disease characterized by impaired phenylalanine (Phe) metabolism, leading to severe mental retardation. When diagnosed early in life and adequately treated by a Phe-restricted diet, mental development is within normal ranges. However, outcome remains suboptimal, and the strict treatment reduces quality of life. We found that in PKU patients, higher blood Phe concentrations were associated with less 11C-tyrosine transport, which in turn was strongly related with less cerebral protein synthesis (CPS). Moreover, higher brain Phe concentrations were strongly associated with less CPS. These associations were further studied in a PKU mouse model. Untreated PKU mice showed several characteristic biochemical changes in blood and brain. Unexpectedly, these mice did not show learning and memory deficits in behavioral tasks. To clarify these phenotypic differences, we studied the pCREB/CREB signaling system, which connects biochemical markers to learning and memory. While the pCREB/CREB system was less active in PKU mice under baseline conditions, its activity normalized after behavioral testing. These results suggest that PKU mice maintain learning and memory by upregulating the pCREB/CREB system. In behavioral tasks associated with monoaminergic neurotransmitter signaling, PKU mice displayed several deficits, which were paralleled by reduced brain concentrations of these neurotransmitters. A monotherapeutic approach to restore these abnormalities was ineffective, suggesting that multiple interventions may be required. Together, our findings suggest several targets for developing mechanism-based therapies in PKU. Such therapies will likely improve treatment outcome and quality of life.

AB - This thesis investigates the mechanisms by which phenylketonuria (PKU) results in brain dysfunction. PKU is an inherited disease characterized by impaired phenylalanine (Phe) metabolism, leading to severe mental retardation. When diagnosed early in life and adequately treated by a Phe-restricted diet, mental development is within normal ranges. However, outcome remains suboptimal, and the strict treatment reduces quality of life. We found that in PKU patients, higher blood Phe concentrations were associated with less 11C-tyrosine transport, which in turn was strongly related with less cerebral protein synthesis (CPS). Moreover, higher brain Phe concentrations were strongly associated with less CPS. These associations were further studied in a PKU mouse model. Untreated PKU mice showed several characteristic biochemical changes in blood and brain. Unexpectedly, these mice did not show learning and memory deficits in behavioral tasks. To clarify these phenotypic differences, we studied the pCREB/CREB signaling system, which connects biochemical markers to learning and memory. While the pCREB/CREB system was less active in PKU mice under baseline conditions, its activity normalized after behavioral testing. These results suggest that PKU mice maintain learning and memory by upregulating the pCREB/CREB system. In behavioral tasks associated with monoaminergic neurotransmitter signaling, PKU mice displayed several deficits, which were paralleled by reduced brain concentrations of these neurotransmitters. A monotherapeutic approach to restore these abnormalities was ineffective, suggesting that multiple interventions may be required. Together, our findings suggest several targets for developing mechanism-based therapies in PKU. Such therapies will likely improve treatment outcome and quality of life.

M3 - Thesis fully internal (DIV)

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