Study of Huntington related peptide interaction with membranes by combining spectroscopic and structural biophysics techniques.

• Grant number: 23/10323-3
• Support Opportunities: Research Grants - Visiting Researcher Grant - International
• Start date: October 02, 2023
• End date: October 19, 2023
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Rosangela Itri
• Grantee: Rosangela Itri
• Visiting researcher: Ana Margarida Pereira de Melo
• Visiting researcher institution: Instituto Superior Técnico (IST), Portugal
• Host Institution: Instituto de Física (IF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an abnormal CAG trinucleotide expansion within the first exon of the huntingtin gene. Specifically, pathological expansions above a critical CAG-repeat length of about 37 lead to the expression of a mutant huntingtin (mhtt) protein with an expanded polyglutamine (polyQ) domain, which ultimately forms amyloid-like fibrils and intracellular inclusion bodies. Although htt has a large size (more than 3000 amino acid residues), aberrant splicing or proteolytic cleavage of mhtt proteins result in highly toxic htt fragments spanning exon 1 (httex1), which are sufficient to replicate much of HD's pathology.Unfortunately, no effective treatment has been developed for this fatal pathology so far, since the precise cause or mechanism(s) by which httex1 contributes to neurodegeneration remain elusive. Here, we inted to explore the role of membrane with different lipid compositions to act as two-dimensional catalyst of httex1 aggregation into fibrils and/or to compromise the membrane structure integrity. Synchrotron radiation oriented circular dichroism (SR-OCD) will be performed at CEDRO beamline in the Brazilian Synchrotron Sirius, Campinas, SP, in collaboration with Dra. Juliana Yoneda, to provide the alignment of the peptide with the lipid membrane, as well as its conformation during interaction aiming to underline the lipid dependent-interaction mechanism. SAXS technique at Crystallography Lab at IFUSP will be used to define the lipid bilayer structure of different lipid compositions. Further, the invited researcher, profa Dra. Ana Melo, will participate as a speaker in the 47th Annual Meeting of Brazilian Biophysical Society (SBBf), which will be held at UNICAMP Convention Center from 19 to 22 October 2023 (Scientific Program | 47sbbf (sbbf47.org.br) (AU)