Odel for testing compounds that generically counteract the toxicity of protein aggregates. The exposure of nematodes to standard amyloid binding ligands, including thioflavin T and curcumin, has a beneficial effect on the regulators of protein homeostasis and significantly improves the worms lifespan 1326631 [7]. Although C. elegans has been widely employed to investigate a number of neurodegenerative diseases, its application to the study of systemic amyloidoses related to human proteins, i.e. lysozyme, monoclonal light chains, b2-microglobulin (b2-m) and transthyretin (TTR), is limited. A transgenic C. elegans strain expressing wild type human TTR was generated to investigate its putative protective role against the amyloid beta (Ab) toxicity rather than testing the intrinsic amyloidogenic propensity of TTR [8]. Link and his collaborators Chebulagic acid custom synthesis showed that the expression of human wild type or Ala60-mutated TTR protected a C. elegans transgenic strain from the paralysis induced by Ab3?2 expression but was not associated, per se, to the formation of amyloid deposits [8] or to any specific phenotype [9].C. elegans Models for b2-m AmyloidosisIn vivo models of systemic amyloidosis are urgently needed and this is particularly required for b2-m associated disease where any attempt to generate an animal model to recapitulate the key molecular aspects of the pathology have currently failed [10]. b2-m is the non-covalently bound light chain of the major histocompatibility complex class I (MHCI). In patients under chronic haemodialysis treatment, it dissociates and converts into amyloid fibrils whose deposition in osteoarticular tissues causes the pathological condition known as dialysis-related amyloidosis (DRA) [11]. Extensive work has been carried out to elucidate the biophysical basis of the propensity of b2-m to make amyloid fibrils in vitro and identify the specific contribution of a single amino acid residue to the aggregation TA 02 kinetics. We have shown that, under physiological like conditions, b2-m monomers, spontaneously, form oligomeric species which are on the pathway of fibril formation [12,13]. A modest acidification, consistent with the patho-physiologic fluctuations of the pH within the periarticular tissue, or a small increase of temperature, that can often occur during the haemodialysis treatment, strongly enhanced the protein polymerization [14]. The generation of the first transgenic C. elegans strains constitutively expressing the wild type b2-m (WT) and two highly amyloidogenic variants, P32G and the truncated form at the 6th N-terminal residue (DN6), represent our method to fill the gap existing between the molecular features analyzed in vitro and the pathogenic events observed in patients. The P32G variant [15], which was designed to highlight the role of the native cisHis31-Pro32 peptide bond in the fibrillogenesis, enhanced the in vitro amyloidogenic potential of wild type protein. DN6 is a ubiquitous constituent of b2-m amyloid deposits in patients affected by DRA and, due to its capacity to act as a seed in the fibrillogenesis of full length b2-m, it could have a crucial role in dictating the clinical history of the disease [16]. C. elegans represents a suitable organism to study the tissue damage associated to b2-m self aggregation 12926553 since it lacks the MHCI complex and therefore all the b2-m is expressed in a state not bound by the MHCI heavy chain. The abundance of notbound b2-m mimics what occurs during haemodialysis, where circulati.Odel for testing compounds that generically counteract the toxicity of protein aggregates. The exposure of nematodes to standard amyloid binding ligands, including thioflavin T and curcumin, has a beneficial effect on the regulators of protein homeostasis and significantly improves the worms lifespan 1326631 [7]. Although C. elegans has been widely employed to investigate a number of neurodegenerative diseases, its application to the study of systemic amyloidoses related to human proteins, i.e. lysozyme, monoclonal light chains, b2-microglobulin (b2-m) and transthyretin (TTR), is limited. A transgenic C. elegans strain expressing wild type human TTR was generated to investigate its putative protective role against the amyloid beta (Ab) toxicity rather than testing the intrinsic amyloidogenic propensity of TTR [8]. Link and his collaborators showed that the expression of human wild type or Ala60-mutated TTR protected a C. elegans transgenic strain from the paralysis induced by Ab3?2 expression but was not associated, per se, to the formation of amyloid deposits [8] or to any specific phenotype [9].C. elegans Models for b2-m AmyloidosisIn vivo models of systemic amyloidosis are urgently needed and this is particularly required for b2-m associated disease where any attempt to generate an animal model to recapitulate the key molecular aspects of the pathology have currently failed [10]. b2-m is the non-covalently bound light chain of the major histocompatibility complex class I (MHCI). In patients under chronic haemodialysis treatment, it dissociates and converts into amyloid fibrils whose deposition in osteoarticular tissues causes the pathological condition known as dialysis-related amyloidosis (DRA) [11]. Extensive work has been carried out to elucidate the biophysical basis of the propensity of b2-m to make amyloid fibrils in vitro and identify the specific contribution of a single amino acid residue to the aggregation kinetics. We have shown that, under physiological like conditions, b2-m monomers, spontaneously, form oligomeric species which are on the pathway of fibril formation [12,13]. A modest acidification, consistent with the patho-physiologic fluctuations of the pH within the periarticular tissue, or a small increase of temperature, that can often occur during the haemodialysis treatment, strongly enhanced the protein polymerization [14]. The generation of the first transgenic C. elegans strains constitutively expressing the wild type b2-m (WT) and two highly amyloidogenic variants, P32G and the truncated form at the 6th N-terminal residue (DN6), represent our method to fill the gap existing between the molecular features analyzed in vitro and the pathogenic events observed in patients. The P32G variant [15], which was designed to highlight the role of the native cisHis31-Pro32 peptide bond in the fibrillogenesis, enhanced the in vitro amyloidogenic potential of wild type protein. DN6 is a ubiquitous constituent of b2-m amyloid deposits in patients affected by DRA and, due to its capacity to act as a seed in the fibrillogenesis of full length b2-m, it could have a crucial role in dictating the clinical history of the disease [16]. C. elegans represents a suitable organism to study the tissue damage associated to b2-m self aggregation 12926553 since it lacks the MHCI complex and therefore all the b2-m is expressed in a state not bound by the MHCI heavy chain. The abundance of notbound b2-m mimics what occurs during haemodialysis, where circulati.
