Targeting phenylalanine assemblies as a prospective disease-modifying therapy for phenylketonuria

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Phenylketonuria (PKU) is a genetic disorder causing phenylalanine accumulation, leading to severe neurological and cognitive deficits.
• Current treatments for PKU are insufficient, necessitating novel therapeutic strategies.
• Previously identified amyloid-like toxic assemblies of phenylalanine suggest a new therapeutic target.

Purpose of the Study:

• To identify compounds that inhibit phenylalanine aggregation.
• To evaluate the efficacy of a promising compound, Morin hydrate, in a phenylketonuria mouse model.

Main Methods:

• High-throughput screening to identify inhibitors of phenylalanine aggregation.
• In vivo testing of Morin hydrate in a phenylketonuria mouse model.
• Assessment of cognitive and motor function, brain phenylalanine deposits, and key neuronal markers.

Main Results:

• Morin hydrate significantly improved cognitive and motor functions in the PKU mouse model.
• Treatment with Morin hydrate reduced the number of phenylalanine deposits in the brain.
• Neuronal and neurotransmitter markers (dopaminergic, adrenergic) recovered despite sustained high phenylalanine levels.

Conclusions:

• Morin hydrate effectively halts phenylalanine aggregation, suggesting the toxic role of these assemblies in PKU.
• Morin hydrate demonstrates disease-modifying potential for PKU by targeting phenylalanine assemblies, independent of phenylalanine levels.
• These findings open new therapeutic avenues for phenylketonuria.