Skip to Main content Skip to Navigation
Theses

How protein misfolding can lead to cellular dysfunction and disease : the case of islet amyloid polypeptide involved in type 2 diabetes mellitus

Abstract : To have a biological function, a protein folds into a specific structure. The cell controls the correct folding of the proteins and has mechanisms to detect and eliminate misfolded proteins; nevertheless some proteins achieve to avoid this control process. Amyloid proteins are misfolded proteins that form a characteristic type of elongated amyloid fibril; depending on the protein sequence and the site of amyloid deposition they are related to different human diseases. Islet amyloid polypeptide (IAPP) a 37 amino acid peptide co-produced and co-secreted with insulin by β-cells, is involve in type 2 diabetes disease and belongs to this group of amyloid proteins. The fibrils are formed in the pancreatic islet. However the conditions under which the fibers are formed and their cytotoxicity in other cells are still unknown. Here we show that the human IAPP flanking peptides, produced during hIAPP maturation, N-terminal and C-terminal are not amyloidogenic and the toxicity of human IAPP in different cell lines. We find through biophysical assays ThT, TEM and CD that N-terminal and C-terminal residues of IAPP do not form fibrils in solution, in artificial vesicles or in cells and do not modify hIAPP toxic effect. For the toxicity of hIAPP we use Ins-1 (β-cells), SHSY5 (neuronal), F442A and 3T3L1 (adipose), mhAT3F (hepatic) and C2C12 (muscle) lines. We observe fibril formation in all cell lines, however the toxicity do not related directly with the presence of fibril. We anticipate our assay to be a starting point for more in vitro studies in different cells lines. Furthermore, IAPP fibril inhibition could be a target for anti-amyloid drug development.
Complete list of metadata

https://tel.archives-ouvertes.fr/tel-03375647
Contributor : Abes Star :  Contact
Submitted on : Wednesday, October 13, 2021 - 1:01:27 AM
Last modification on : Friday, December 3, 2021 - 11:43:18 AM

File

SALAZAR_VAZQUEZ_Lilian_Shadai_...
Version validated by the jury (STAR)

Identifiers

  • HAL Id : tel-03375647, version 1

Citation

Lilian Shadai Salazar Vázquez. How protein misfolding can lead to cellular dysfunction and disease : the case of islet amyloid polypeptide involved in type 2 diabetes mellitus. Medicinal Chemistry. Sorbonne Université, 2019. English. ⟨NNT : 2019SORUS371⟩. ⟨tel-03375647⟩

Share

Metrics

Record views

111

Files downloads

67