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Role of Nrf2 in Neurodegeneration

Subjects: Molecular Biology View times: 73
Submitted by: Camila Xu

Abstract

Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) are characterized by the presence of three main hallmarks: oxidative stress, neuroinflammation, and alterations in cellular proteostasis. Ever since its discovery, the transcription factor Nrf2 (nuclear factor erythroid-derived 2-like 2) has been implicated in processes associated with redox balance, inflammation, and proteostasis, among other mechanisms, representing a pleiotropic transcription factor. The function of Nrf2 is altered in these neurodegenerative diseases, and pharmacological activation of Nrf2 alleviates those three main hallmarks involved in neurodegeneration through the upregulation of antioxidant defenses, inhibition of inflammation, and modulation of protein homeostasis.

This webinar on Nrf2 will emphasize the importance of this transcription factor in neurodegenerative diseases and also highlight existing pharmacological components that can modify the Nrf2 signaling pathway.

1. Introduction

The third Biomolecules webinar, entitled “Role of Nrf2 in Neurodegeneration: Novel Molecular Mechanisms and Therapeutic Approaches", was held on Friday 16 October, 2020. It was chaired by Prof. Dr. Isabel Lastres-Becker.

This online seminar emphasized the importance of Nrf2 transcription factor in neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, and highlighted existing pharmacological components targeting the Nrf2 signaling pathway.

After an introduction given by the chair, Prof. Dr. Manuela G. López presented her research on “NRF2: a therapeutic target for Alzheimer's disease”. Dr. Fabio Di Domenico followed with a presentation on “The aberrant crosstalk between PERK and Nrf2 in Down syndrome: A novel target for therapeutic intervention”. Prof. Dr. Bianca Marchetti was the final speaker and spoke about “Resilience of Nrf2-ARE axis and Wnt/β-catenin intertwined signaling cascades to fight ageing and nigrostriatal degeneration in Parkinson’s disease”.

2. The details of experts

Dr. Lastres-Becker has more than 20 years of experience in the field of neurodegenerative diseases. The study of neurodegenerative diseases has been at the focus from the beginning of her doctoral thesis and until now, the thread that has guided her entire scientific career. Her work is focused on the molecular bases of neurodegeneration related to proteinopathy, neuroinflammation, and oxidative stress. She is the head of the laboratory of “New therapeutic strategies in neurodegenerative diseases: Parkinson's disease (PD), tauopathies and amyotrophic lateral sclerosis (ALS)”. The research projects she has developed have a multidisciplinary approach that combines basic and translational research, using cell culture techniques, murine models (transgenic mice and adeno-associated viral vectors), and postmortem samples from patients with AD, PD, and ALS. She is engaged in the development of advanced biological markers, new drugs, and appropriate technology toward establishing treatments for those diseases.

Department of Biochemistry, School of Medicine, Universidad Autonoma de Madrid, Madrid, Spain.

Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Sanitaria La Paz (IdiPaz), Instituto de Investigaciones Biomédicas "Alberto Sols", UAM-CSIC, Madrid, Spain.

Dr. Bianca Maria Marchetti is a Full Professor of Pharmacology at the School of Medicine, University of Catania, Italy, and directs the research activities of the Molecular and Experimental Neuropharmacology Section at the OASI Institute—IRCCS-Troina. Dr. Marchetti graduated in Pharmacy (1974, Rome) and won a ministerial research grant in 1975. She then moved to the University of Catania (1976) to carry out scientific didactic activities at the Institute of Pharmacology. She obtained her Ph.D. in Molecular Endocrinology in 1987 from Laval University, Quebec, Canada, and continued post-doctoral research activities, as a visiting Scientist, at the Department of Physiology and Immunology, University of Alabama at Birmingham, US, and as a visiting Professor at the Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. Winner of the Free Competition for Qualifications and Exams (1996), she has held the position of Associate Professor of Pharmacology since November 1998, first at the University of Sassari, and since November 2008 at the University of Catania. She obtained the National Scientific Qualification in the role of Full Professor of Pharmacology in 2016. Studies of the last decades concentrated on glia-neuron dialogue in Parkinson’s disease with a specific focus on Nrf2/Wnt-signaling axis, its crosstalk with inflammatory and survival pathways in neuroprotection, the activation of adult neurogenesis, and the development of therapeutic strategies to counteract progressive neuronal degeneration and boost the inherent self-protective and reparative capacities of the aged, injured brain.

Department of Biomedical and Biotechnological Sciences (BIOMETEC), Pharmacology Section, University of Catania Medical School, Italy.

Dr. Manuela G. Lopez is a Full Professor of Pharmacology at the School of Medicine, Autonomous University of Madrid (UAM), Spain. She is the current Director of the Institute Teofilo Hernando for R&D of drugs and trustee of the Foundation Teofilo Hernando. Her research focuses on the R&D of neuroprotective drugs for neurodegenerative diseases and cerebral ischemia, from the identification of new potentially therapeutic targets to the dissection of the mechanism of action of drugs already marketed or newly synthesized. She has published over 150 scientific articles and has an h-index of 48. She is a co-inventor of 11 patents related to neuroprotective compounds for neurodegenerative diseases and stroke and has participated in over thirty research projects as IP or collaborator. She belongs to the Spanish Network of Excellence “Translational research network on the pharmacological regulation of NRF2 in non-communicable diseases” and is currently the coordinator of the multidisciplinary project “Development of NRF2-activating drugs for innovative therapies for Alzheimer's disease” funded by the Community of Madrid and the European Union. She also collaborates with several pharmaceutical companies as a scientific expert and consultant and was a former member of The European Network on Oxidative Stress and Redox Biology Research. At the UAM, she has promoted the teaching of pharmacology, coordinates the Master’s Degree in Pharmacological Research, and has mentored 17 Ph.D. theses and 16 Master’s theses.

Instituto Teófilo Hernando for Drug Discovery, Universidad Autónoma de Madrid, Madrid, Spain.

Dr. Di Domenico graduated at Sapienza University of Rome where he also obtained his PhD degree in Biochemistry in 2009. Before beginning his current position at Sapienza University of Rome, he performed research under the supervision of Prof. Butterfield at University of Kentucky. Dr. Di Domenico’s research is currently focused on understanding the role of defective proteostasis in the development of Alzheimer’s-like dementia in order to propose novel effective therapeutic approaches that might ameliorate cognitive decline. Collected data from Dr. Di Domenico’s laboratory postulate that aberrant proteostasis, observed in both Alzheimer’s and Down syndrome patients, is strictly associated with the increase of oxidative damage as result of compromised antioxidant response and faulty protein degradative systems. Recently, his studies revealed that chronic induction of the unfolded protein response has a prominent role in the development of AD-like dementia in DS brain. Indeed, the pharmacological rescue of UPR function leads to the reduction in neuropathological hallmarks and to decrease in protein oxidation in a mechanism involving the Nrf2 antioxidant response.

Department of Biochemical Sciences , Sapienza University of Rome, Italy.

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Genetics ; – Created: 09 Jul 2020; Latest updated: 17 Jul 2020