Doxycycline hinders phenylalanine fibril assemblies revealing a potential novel therapeutic approach in phenylketonuria.
A new paradigm for the aetiopathology of phenylketonuria suggests the presence of amyloid-like assemblies in the brains of transgenic mouse models and patients with phenylketonuria, possibly shedding light on the selective cognitive deficit associated with this disease. Paralleling the amyloidogenic route that identifies different stages of peptide aggregation, corresponding to different levels of toxicity, we experimentally address for the first time, the physico-chemical properties of phenylalanine aggregates via Small Angle, Wide Angle X-ray Scattering and Atomic Force Microscopy. Results are consistent with the presence of well-structured, aligned fibres generated by milliMolar concentrations of phenylalanine. Moreover, the amyloid-modulating doxycycline agent affects the local structure of phenylalanine aggregates, preventing the formation of well-ordered crystalline structures. Phenylalanine assemblies prove toxic in vitro to immortalized cell lines and primary neuronal cells. Furthermore, these assemblies also cause dendritic sprouting alterations and synaptic protein impairment in neurons. Doxycycline counteracts these toxic effects, suggesting an approach for the development of future innovative non-dietary preventive therapies.
Department of Molecular Biochemistry and Pharmacology, Via Giuseppe La Masa 19, Milano, 20156, Italy.
Ada
A
De Luigi
Department of Environmental Health Sciences, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, 20156, Italy.
Alessandro
A
Mariani
Department of Environmental Health Sciences, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, 20156, Italy.
Massimiliano
M
De Paola
Department of Environmental Health Sciences, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, 20156, Italy.
Andrea
A
Re Depaolini
Department of Molecular Biochemistry and Pharmacology, Via Giuseppe La Masa 19, Milano, 20156, Italy.
Laura
L
Colombo
Department of Molecular Biochemistry and Pharmacology, Via Giuseppe La Masa 19, Milano, 20156, Italy.
Luca
L
Russo
Department of Medical Biotechnology and Translational Medicine, University of Milan, LITA, Segrate, 20090, Italy.
Valeria
V
Rondelli
Department of Medical Biotechnology and Translational Medicine, University of Milan, LITA, Segrate, 20090, Italy.
Paola
P
Brocca
Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences.|Department of Oral Biology, The Goldschleger School of Dental Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Lihi
L
Adler-Abramovich
Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences.
Ehud
E
Gazit
Department of Medical Biotechnology and Translational Medicine, University of Milan, LITA, Segrate, 20090, Italy.
Elena
E
Del Favero
Department of Medical Biotechnology and Translational Medicine, University of Milan, LITA, Segrate, 20090, Italy.
Laura
L
Cantù
Department of Molecular Biochemistry and Pharmacology, Via Giuseppe La Masa 19, Milano, 20156, Italy.
Mario
M
Salmona
D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D004318:Doxycycline / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010649:Phenylalanine / Q000378:metabolism*; D010661:Phenylketonurias / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013569:Synapses / Q000378:metabolism* / Q000473:pathology
D000682:Amyloid; D010649:Phenylalanine; D004318:Doxycycline