Lessons learned from protein aggregation: toward technological and biomedical applications

ÁVILA, C.; CHAVES S.; SOCIAS, S.B.; VERA-PINGITORE E.; GONZÁLEZ-LIZÁRRAGA F.; VERA C.; PLOPER D.; CHEHÍN R.

Biophysical Reviews

springer

Lugar: Berlin; Año: 2017 vol. 9 p. 501 - 515

1867-2469

Abstract The close relationship between protein aggregationand neurodegenerative diseases has been the driving forcebehind the renewed interest in a field where biophysics, neurobiologyand nanotechnology converge in the study of theaggregate state. On one hand, knowledge of the molecularprinciples that govern the processes of protein aggregationhas a direct impact on the design of new drugs for highincidencepathologies that currently can only be treated palliatively.On the other hand, exploiting the benefits of proteinaggregation in the design of new nanomaterials could have astrong impact on biotechnology. Here we review the contributionsof our research group on novel neuroprotective strategiesdeveloped using a purely biophysical approach. First, we examinehow doxycycline, a well-known and innocuous antibiotic,can reshape α-synuclein oligomers into non-toxic highmolecular-weight species with decreased ability to destabilizebiological membranes, affect cell viability and form additionaltoxic species. This mechanism can be exploited to diminishthe toxicity of α-synuclein oligomers in Parkinson?s disease.Second, we discuss a novel function in proteostasis for extracellularglyceraldehyde 3-phosphate dehydrogenase(GAPDH) in combination with a specific glycosaminoglycan(GAG) present in the extracellular matrix. GAPDH, by changingits quaternary structure from a tetramer to protofibrillarassembly, can kidnap toxic species of α-synuclein, and therebyinterfere with the spreading of the disease. Finally, wereview a brighter side of protein aggregation, that ofexploiting the physicochemical advantages of amyloid aggregatesas nanomaterials. For this,we designed a new generationof insoluble biocatalysts based on the binding of photoimmobilizedenzymes onto hybrid protein:GAG amyloidnanofibrils. These new nanomaterials can be easily functionalizedby attaching different enzymes through dityrosine covalentbonds.