Project ID NS-MH2023_21


Co Supervisor 1A Faculty of Dentistry/Centre for Oral, Clinical & Translational SciencesWebsite

Co Supervisor 1B FoLSM/Cardiovascular and Metabolic Medicine and SciencesWebsite

Unveiling the Role of Protein Disorder in Brain Calcifications of Neurogenerative Diseases

There is a potential link between neurodegenerative diseases and disordered proteins forming amyloids, which subsequently trigger calcification of brain tissues. In our research laboratories, we have discovered indicative calcification patterns occurring in pineal glands of Alzheimer’s disease (AD) and frontotemporal degeneration patients (Figure 1). However, there is still a great lack of knowledge on the role of protein disorder and organic-inorganic interactions in brain calcifications.

a) Investigate protein conformations and mechanisms at the molecular level within brain tissues including the pineal glands of AD patients compared to healthy controls.
b) Carry out further sophisticated high-resolution imaging and proteomics techniques to study the structure of the organic-inorganic interface of the brain calcification.
c) DNA isolation from pinealocytes, astrocytes, and glial cells to understand the mechanisms of calcification.
d) Fabricate in-vitro models based on proteins derived from brain tissues to investigate calcification at multiple length scales.

Laser capture microdissection (LMD) and proteomics.
High-resolution electron microscopy, material development.
Protein conformation studies: Circular Dichroism, Fourier Transform Infra-Red imaging, Dynamic Light Scattering.

Year 1– Study proteomics and gene expression on diseased tissues (LMD) alongside with advanced imaging techniques to characterise calcification in tissues in pineal glands and brain.
Year 2– Analyse the extracted proteins from diseased and healthy tissues and isolate RNA from specific areas around calcification.
Year 3– Employ epigenetic approaches to investigate the cells surrounding the calcified tissues.
Year 4– Synthesise proteins that are identified in diseased tissues and create in-vitro models for calcification.

Representative Publications

Elsharkawy, S., Al-Jawad, M., Pantano, M.F. et al. Protein disorder–order interplay to guide the growth of hierarchical mineralized structures. Nature Communications 9, 2145 (2018).

Kapustin AN, Chatrou ML, Drozdov I, Zheng Y, Davidson SM, Soong D, Furmanik M, Sanchis P, De Rosales RT, Alvarez-Hernandez D, Shroff R, Yin X, Muller K, Skepper JN, Mayr M, Reutelingsperger CP, Chester A, Bertazzo S, Schurgers LJ, Shanahan CM. (2015) Vascular smooth muscle cell calcification is mediated by regulated exosome secretion. Circulation Research. 116(8):1312-23. DOI: 10.1161/CIRCRESAHA.116.305012