Three-dimensional structure of the lithostathine protofibril, a protein involved in Alzheimer's disease

Abstract

Neurodegenerative diseases are characterized by the presence of filamentous aggregates of proteins. We previously established that lithostathine is a protein overexpressed in the pre‐clinical stages of Alzheimer's disease. Furthermore, it is present in the pathognomonic lesions associated with Alzheimer's disease. After self‐proteolysis, the N‐terminally truncated form of lithostathine leads to the formation of fibrillar aggregates. Here we observed using atomic force microscopy that these aggregates consisted of a network of protofibrils, each of which had a twisted appearance. Electron microscopy and image analysis showed that this twisted protofibril has a quadruple helical structure. Three‐dimensional X‐ray structural data and the results of biochemical experiments showed that when forming a protofibril, lithostathine was first assembled via lateral hydrophobic interactions into a tetramer. Each tetramer then linked up with another tetramer as the result of longitudinal electrostatic interactions. All these results were used to build a structural model for the lithostathine protofibril called the quadruple‐helical filament (QHF‐litho). In conclusion, lithostathine strongly resembles the prion protein in its dramatic proteolysis and amyloid proteins in its ability to form fibrils.

Distribution of lithostathine in the mouse lemur brain with aging and Alzheimer's-like pathology

“…Lithostathine-immunoreactive neurons were observed at the vicinity of diffuse plaques but never detected into amyloid plaques or neurofibrillary tangles as it has been shown earlier (de la Monte et al, 1990;Duplan et al, 2001;Ozturk et al, 1989).…”

“…This function may be related to a putative involvement of lithostathine in plasticity mechanisms as suggested by De La Monte et al (de la Monte et al, 1990) or evidenced for an homologous regenerating protein Reg2 in central nervous system (Nishimune et al, 2000). In contrast, based on the pro-inflammatory property of lithostathine and its link to pro-inflammatory cytokines overexpression (Duplan et al, 2001), we propose that accumulation of lithostathine in the brain would also be an indirect consequence of peculiar chronic inflammatory status during aging (Franceschi and Bonafe, 2003;Giunta et al, 2008;Giunta, 2006). All in all, these findings indicate that lithostathine represents an interesting protein to be investigated for its role in aging.…”

“…Studies were mostly dedicated to Alzheimer's disease (de la Monte et al, 1990;Duplan et al, 2001;Ozturk et al, 1989) or Creutzfeldt-Jakob disease (CJD) (Laurine et al, 2003), but not to normal aging.…”

“…Protein expression depends on the developing human brain and the presence of neurofibrillary tangles in the pathogenesis of Alzheimer's disease (AD). More recently, accumulation of the protein was concomitant with the formation of Aβ and prion amyloid plaques in patients with AD and prion diseases (Duplan et al, 2001;Laurine et al, 2003). While the accumulation of the protein has been linked to the inflammatory process of the pathogenesis of AD (Duplan et al, 2001), little is known concerning the expression pattern of lithostathine in normal aging.…”

“…The cleavage produces a soluble N-terminal undecapeptide and a C-terminal part of 133 amino acids that precipitate and form protease-K-resistant fibrils at physiological pH (Gregoire et al, 2001). Although its physiological function in digestive organs remains debated (Bimmler et al, 1997;De Reggi et al, 1998), the protein tightly binds calcium carbonate crystals, suggesting an inhibitory activity on CaCO 3 crystal growth, thus preventing lithiasis (Bernard et al, 1992;Geider et al, 1996;Gerbaud et 4 al., 2000;Lee et al, 2003) .…”