Lessons learned from protein aggregation: toward technological and biomedical applications

ÁVILA C.; CHAVES S.; SOCÍAS B.; VERA PINGITORE E.; GONZÁLEZ LIZÁRRAGA M.F.; VERA C.; PLOPER D.; CHEHÍN R.

Biophysical reviews

SPRINGER

Año: 2017 vol. 9 p. 501 - 515

1867-2450

The close relationship between protein aggregationand neurodegenerative diseases has been the driving forcebehind the renewed interest in a field where biophysics, neu-robiology and 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 high-incidence pathologies that currently can only be treated pal-liatively. 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 contribu-tions of our research group on novel neuroprotective strategiesdeveloped using a purely biophysical approach. First, we ex-amine how doxycycline, a well-known and innocuous antibi-otic, can reshape α-synuclein oligomers into non-toxic high-molecular-weight species with decreased ability to destabilizebiologicalmembranes, affect cell viability and formadditionaltoxic species. This mechanism can be exploited to diminishthe toxicity of α-synuclein oligomers in Parkinson?sdisease.Second, we discuss a novel function in proteostasis for extra-cellular glyceraldehyde 3-phosphate dehydrogenase(GAPDH) in combination with a specific glycosaminoglycan(GAG) present in the extracellular matrix. GAPDH, by chang-ing its quaternary structure from a tetramer to protofibrillarassembly, can kidnap toxic species of α-synuclein, and there-by interfere with the spreading of the disease. Finally, wereview a brighter side of protein aggregation, that ofexploiting the physicochemical advantages of amyloid aggre-gates as nanomaterials. For this,we designed a new generationof insoluble biocatalysts based on the binding of photo-immobilized enzymes onto hybrid protein:GAG amyloidnanofibrils. These new nanomaterials can be easily function-alized by attaching different enzymes through dityrosine co-valent bonds.