Seminari de Recerca "Neurotoxicity of microbial ureases and implications for neurodegenerative diseases"

Dr. Celia R. Carlini, Senior Researcher Pontifical Catholic University of Rio Grande do Sul, Brazil

Ureases of pathogenic microorganisms act as virulence factors mainly because their enzymatic activity enables colonization of the host. The bacteria Proteus mirabilis (Pm) and Helicobacter pylori (Hp) produce large amounts of urease (PMU and HPU, respectively). Epidemiologic studies have shown that (i) Parkinson’s disease (PD) and Alzheimer’s disease (AD) patients are more likely to be infected with Hp than healthy people; (ii) when Hp-positive, PD patients display worse motor functions and AD patients more severe cognitive impairment than Hp-negative patients; (iii) eradication of Hp improves motor function and cognitive impairment in PD and AD patients, respectively. Moreover, studies in animal models have found that: (a) a Hp conditioned medium given ip to rats caused hyperphosphorylation of tau and increased GSK-3â activity in the  hippocampus, hallmarks of AD; and (b) the oral administration to mice of a Pm culture induced motor deficits, death of dopaminergic neurons and aggregation of á-synuclein in the brain and intestines, consistent with a PD-like pathology. 

Recently, evidence have mounted for previously unknown non-enzymatic and neurotoxic properties of PMU and HPU. We report that purified PMU and HPU, tested in nanomolar doses, alter intracellular calcium levels and induce production of reactive oxygen species and the cytokines IL-1â and TNF-á in cultures of CNS-derived cells. Mice treated ip with 20 ìg PMU/daily for 1 week showed altered performance in the plus elevated maze, dark-light box and tail suspension behavioral tasks. Rats treated ip with 5 µg HPU/daily for 1 week showed hyperphosphorylation of tau at Ser199, Thr205, and Ser396 sites and overexpression of Iba1 (microglia activation marker) in hippocampal homogenates. Behavioral tests indicated no cognitive impairments, suggesting a “prodromic” stage of neuroinflammation.

The data indicate that bacterial ureases may contribute to pathogenesis of neurodegenerative diseases like PD and AD, through their enzymatic (production of toxic ammonia) and/or their non-enzymatic properties (e.g. pro-inflammatory and neurotoxic activities), thus representing potential targets for therapeutic development.

Celia R. Carlini holds a B.Sc. in Biomedical Sciences (1978) and a PhD degree (1985) in Molecular Biology – Protein Chemistry, both from the Federal University of São Paulo – UNIFESP (former Escola Paulista de Medicina), in São Paulo, Brazil. From 1983 to 1997, she was Associate Professor at  Federal University of Rio de Janeiro – UFRJ, Rio de Janeiro, Brazil, and from 1997 to 2012, she was Full Professor at Federal University of Rio Grande do Sul – UFRGS, in Porto Alegre, Brazil. In August 2013, she was hired as a Principal Investigator at the Brain Institute (Instituto do Cérebro – InsCer) and Associate Professor of the School of Medicine at the Pontifical Catholic University of Rio Grande do Sul – PUCRS, Porto Alegre, Brazil, where she coordinates the Laboratory of Neurotoxins.

She has experience in purification and physicochemical characterization of enzymes, proteins and peptides, having dedicated about 40 years to the study of ureases and derived peptides. Her group has pioneered studies that demonstrated that ureases from different sources are multifunctional toxins display non-enzymatic biological properties, such as neurotoxicity and pro-inflammatory activity.  In the last 15 years, she has focused her attention on ureases from plants and human pathogens and on ureases-derived peptides, using in vivo and in vitro models. Concerning bacterial ureases, her scientific motivation is to understand the possible contribution of these proteins to pathologies with repercussions on the central nervous system.

In the last 10 years, the applicant has published 59 articles (2012-2022) with an average impact factor of 4.154 (JCR 2020), out of a total of 164 published throughout her career. In the Web-of-Sciences database, she has received about 3500 citations and a factor H=31. She has supervised 31 master's degrees, and 34 doctorates and 17 post-docs. 

Host: Dr. Miquel Vila Bover - Dr. Ariadna Laguna Tuset, Neurodegenerative Diseases Research Group (VHIR)

Online connection: https://gencat.zoom.us/j/99969384334