Biology subjects

Natale, C.

Publications and source records attributed to Natale, C..

3 recordsLinked to original sources

bioRxiv2024

Modeling Immunoglobulin light chain amyloidosis in Caenorhabditis elegans

Cardiomyopathy determines the prognosis of patients with immunoglobulin light chain (AL) amyloidosis, a rare systemic disease caused by the misfolding and deposition of monoclonal light chains (LCs). The reasons underlining their cardiac tropism remain unknown, and an animal model recapitulating the main pathological features of AL amyloidosis is instrumental. Taking advantage of the similarities between the vertebrate heart and C. elegans pharynx, we developed a new transgenic nematode expressing a human amyloidogenic {lambda} LC whose sequence was deduced from a patient suffering from AL amyloidosis with cardiac involvement (MNH). Strains expressing a non-amyloidogenic LC (MNM) or the empty vector only (MNV) were generated as controls. At variance with controls, LCs expressed in the body-wall muscle of MNH worms formed native soluble dimeric assemblies, which were secreted and reached different organs, including the pharynx. Noteworthy, MNH worms exerted a pharyngeal impairment resembling cardiac functional impairment occurring in patients with AL, accompanied by increased radical oxygen species production and tissue ultrastructural damage. This new animal model can allow the elucidation of the mechanisms underlying the cardiac-specific tropism occurring in AL amyloidosis, providing innovative insights into the pathophysiology.

pathology↗

bioRxiv2020

Role of misfolded tau in the onset and progression of brain toxicity after trauma

Traumatic brain injury (TBI) is associated with widespread tau pathology in about one third of patients. We previously found that TBI induces a transmissible tau pathology (tauTBI), with late cognitive decline and synaptic dysfunction. To understand whether tauTBI is a marker of ongoing neurodegeneration or a driver of functional decline, we employed C. elegans. Brain homogenates from chronic TBI mice, or from mice in which tauTBI had been transmitted by intracerebral inoculation, impaired C. elegans motility and neuromuscular synaptic transmission. Brain homogenates from tau P301L transgenic mice, or pre-aggregated recombinant tau, induced a similar toxic response. Protease digestion or pre-incubation of homogenates with anti-tau antibodies abolished toxicity, and TBI brain homogenates from tau knock-out mice had no toxic effect. These results support a vital role of abnormal tau species in chronic neurodegeneration after TBI and set the groundwork for the development of a C. elegans-based platform for screening anti-tau compounds.

neuroscience↗

bioRxiv2018

Pharmacologic activation of G protein-coupled estrogen receptor inhibits pancreatic ductal adenocarcinoma

Female sex is associated with lower incidence and improved clinical outcomes for many cancer types, including pancreatic ductal adenocarcinoma (PDAC). Although the mechanisms responsible for this sex difference are unknown, recent data suggests nonclassical estrogen signaling through the G Protein-coupled Estrogen Receptor (GPER) is likely involved. Here we used murine syngeneic tumor models and human xenografts to test whether GPER signaling inhibits pancreatic ductal adenocarcinoma (PDAC). Activation of GPER with the specific, small molecule agonist G-1 inhibited PDAC proliferation, depleted c-Myc and programmed death ligand 1 (PD-L1), and increased tumor cell immunogenicity. Systemically delivered G-1 was well tolerated in PDAC bearing mice, significantly prolonged survival, and markedly increased the efficacy of PD-1 targeted immune therapy. We detected GPER protein in a majority of spontaneous human PDAC tumors. These data, coupled with the wide tissue distribution of GPER, and our previous work showing that G-1 inhibits melanoma, suggest that GPER agonists may be useful against many different cancer types.

cancer biology↗