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Drug discovery targeting polyglutamylation in neurodegenerative disorders

Grant number: 18/08434-3
Support type:Regular Research Grants
Duration: September 01, 2020 - August 31, 2021
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Cooperation agreement: Tianjin University
Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
Principal Investigator:Ana Marisa Chudzinski-Tavassi
Grantee:Ana Marisa Chudzinski-Tavassi
Principal investigator abroad: Huiyuan Wu
Institution abroad: Tianjin University (TJU), China
Home Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Associated research grant:15/50040-4 - Rational approach for searching molecular targets involved in inflammatory events and cell survival, AP.PCPE

Abstract

Neurodegenerative diseases (ND) result from the gradual and progressive loss of neural cells, leading to nervous system dysfunction. As the era of aging society is approaching, ever-increasing number of people are afflicted with ND. However, there are currently no effective drugs to cure these diseases. The continual failures in clinical trails of ND drugs that target the pathological hallmarks appeal an alternative target for the drug discovery. Recent studies linked the microtubule disruption in Alzheimer disease (AD), the ND of highest prevalence to a novel protein posttranslational modification-polyglutamylation. Its ectopic activity triggers the microtubule severing in dendrites and the subsequent loss of dendritic spines, which constitute synapses. Notably, the increased polyglutamylation due to dysfunction of its catabolic enzyme- Nna1 underlies the neurodegeneration of Purkinje cell degeneration (pcd) mutant mice. One ongoing research in Dr. Huiyuan Wu's lab at TJU is to identify the possible targets to treat ND caused by hyperglutamylation. An array of methodologies has been established to analyze the synapse loss and neuronal death. Dr. Ana Marisa Chudzinski-Tavassi from Institute Butantan has long been interested in the discovery of antitumor drugs targeting cell death pathways. Her group recently developed a pool of new exogenous molecules and synthetic peptide derivatives targeting the haemostatic system and some of them are already in different phases of drug development process. Beyond haemostasis, some molecules can also modulate other biological systems like the immune system, survival or death pathways, and even tissue regeneration or cytoprotective effects. Several derived-peptides are being used to elucidate potential molecular targets and signaling pathways. In the collaborative project, we explore to target polyglutamylation for treating neurodegeneration with the synthetic peptides developed by Dr. Tavassi's group that show cell-death preventing effects.The following experiments will be conducted in Dr. Wu's Lab: 1) Examine their activities in inhibiting polyglutamylase activity using an in vitro assay; 2) Assess whether the treatments spare or ameliorate the neuronal death in pcd mice using cultured slides; 3) Analyze the cell death pathway in which these peptides are involved to understand the molecular mechanism of neuronal death due to pyperglutamylation.The following exchange activities are proposed to ensure the proper progress of project activities: (1) extensive discussion on the pharmaceutical properties of candidate peptides and determining protocols and data to be collected for each party's interests; (2) discussing the progress of the project and alternative protocols if necessary; (3) analyzing and summarizing the results, discussing the possibility and format of publication, and/or utilizing the results for further funding opportunities. The Health Science Platform at Tianjin University is equipped with state-of-the art instruments to support this research, including cell-culture facility, microtome/cryostat, and confocal-microscopy. Thisresearch will be supported by FASESP funding for Dr. Tavassi and part of the start-up fund for Dr. Wu.This proposal, will pave path for additional funding opportunities that support international collaborations, such as BRICS, NSFC (National Natural Science Foundation of China) grants for international collaboration, and will also attract funding that support ND drug discovery from industries, foundations, and government funding of specific categories. (AU)